Pyridyl and naphthyridyl compounds for inhibiting osteoclast-mediated bone resorption

ABSTRACT

Compounds of the following general structure X-Y-Z-Aryl-A-B, for example, ##STR1## which inhibit osteoclast mediated bone resorption. Specifically, the compounds are useful for treating mammals suffering from a bone condition caused or mediated by increased bone resorption, who are in need of such therapy. The compounds may be administered in oral dosage forms such as tablets, capsules, e.g. sustained release capsules, powders, granules, and suspensions.

This application is a 371 of PCT/U.S. 95/05938, filed on May 12, 1995which is a CIP of U.S. Ser. No. 08/250,218, filed on May 29, 1994 nowabandoned,

BACKGROUND OF THE INVENTION

This invention relates to compounds for inhibiting bone resorption thatis mediated by the action of a class of cells known as osteoclasts.

Osteoclasts are multinucleated cells of up to 400 μm in diameter thatresorb mineralized tissue, chiefly calcium carbonate and calciumphosphate, in vertebrates. They are actively motile cells that migratealong the surface of bone. They can bind to bone, secrete necessaryacids and proteases and thereby cause the actual resorption ofmineralized tissue from the bone.

The pharmacologic activity of these compounds is useful in the treatmentof mammals, including man.

The current major bone diseases of public concern are osteoporosis,hypercalcemia of malignancy, osteopenia due to bone metastases,periodontal disease, hyperparathyroidism, periarticular erosions inrheumatoid arthritis, Paget's disease, immobilization-inducedosteopenia, and glucocorticoid treatment.

All these conditions are characterized by bone loss, resulting from animbalance between bone resorption (breakdown) and bone formation, whichcontinues throughout life at the rate of about 14% per year on theaverage. However, the rate of bone turnover differs from site to site,for example, it is higher in the trabecular bone of the vertebrae andthe alveolar bone in the jaws than in the cortices of the long bones.The potential for bone loss is directly related to turnover and canamount to over 5% per year in vertebrae immediately following menopause,a condition which leads to increased fracture risk.

There are currently 20 million people with detectable fractures of thevertebrae due to osteoporosis in the United States. In addition, thereare 250,000 hip fractures per year attributed to osteoporosis. Thisclinical situation is associated with a 12% mortality rate within thefirst two years, while 30% of the patients require nursing home careafter the fracture.

Individuals suffering from all the conditions listed above would benefitfrom treatment with agents which inhibit bone resorption.

Endothelial cells secrete growth factors that are mitogenic forendothelium and can induce formation of new blood vessels(angiogenesis). Angiogenic stimuli cause the elongation or proliferationof endothelial cells and generation of new vessels.

SUMMARY OF THE INVENTION

The present invention involves a compound of the formula ##STR2##wherein X is selected from the group consisting of ##STR3## Y isselected from the group consisting of C₁₋₈ alkylene,

(CH₂)m--C.tbd.C(CH₂)n,

(CH₂)mCR¹ ═CR² (CH₂)n,

(CH₂)mCR¹ ═CR² (CH₂)nO,

C₀₋₈ alkylene--NR³ --CO--C₀₋₈ alkylene,

C₀₋₈ alkylene--O--C₀₋₈ alkylene,

C₀₋₈ alkylene--NR³ --C₀₋₈ alkylene and

C₀₋₈ alkylene--NR³ --C⁰⁻⁸ alkylene--O--;

A is selected from the group consisting of ##STR4## B is ##STR5## R¹,R², R³ and R⁴ are each independently selected from the group consistingof

hydrogen,

C₁₋₄ alkoxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

amino C₀₋₈ alkyl and

aryl C₀₋₈ alkyl;

R⁵ is selected from the group consisting of

hydrogen,

C₁₋₄ alkoxy C₀₋₆ alkyl,

C₁₋ alkoxycarbonyl C₀₋₆ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

amino C₀₋₈ alkyl,

oxo and

aryl C₀₋₈ alkyl;

R⁶ and R⁷ are each independently selected from the group consisting of:

hydrogen,

C₀₋₆ alkylamino C₀₋₆ alkyl,

C₀₋₆ dialkylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkyloxycarbonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonylamino C₀₋₆ alkyl and

aryl C₀₋₆ alkylcarbonylamino C₀₋₆ alkyl;

R¹² is selected from the group consisting of

hydroxy,

C₁₋₈ alkyloxy,

C₁₋₆ dialkylaminocarbonylmethoxy and

aryl C₁₋₆ dialkylaminocarbonylmethoxy; and

m and n are integers independently chosen from 0-6; provided that whenthe compound is ##STR6## wherein R¹² is hydroxy or C₋₄ alkyloxy, thenX-Y is not NH₂ --(CH₂)₂ --NH--CO--,

BOC--HN--(CH₂)₂ --NH--CO--, ##STR7## and the pharmaceutically acceptablesalts thereof.

In one embodiment is the compound wherein

X is selected from the group consisting of ##STR8## Y is selected fromthe group consisting of C₁₋₃ alkylene,

--C.tbd.C--,

C₀₋₂ alkylene--NH--CO--,

C₀₋₅ alkylene--O--C₀₋₁ alkylene

--NH--C₂₋₄ alkylene and

--NH--C₂₋₄ alkylene--O--;

A is selected from the group consisting of ##STR9## R¹ is selected fromthe group consisting of hydrogen and

C₁₋₄ alkoxy;

R₆ and R₇ are each independently selected from the group consisting of

hydrogen,

--NHCbz,

--NHSO₂ Ph,

--NHC(O)--Ph and

--N(CH₃)--SO₂ Ph; and

m and n are integers independently chosen from 0-6.

In another embodiment is the compound ##STR10## wherein X is selectedfrom the group consisting of ##STR11## Y is selected from the groupconsisting of C₁₋₈ alkylene,

(CH₂)m--C.tbd.C(CH₂)n,

(CH₂)mCR¹ ═CR² (CH₂)n,

(CH₂)mCR¹ ═CR² (CH₂)nO,

C₀₋₈ alkylene--NR³ --CO--C₀₋₈ alkylene,

C₀₋₈ alkylene--O--C₀₋₈ alkylene,

C₀₋₈ alkylene--NR³ --C₀₋₈ alkylene and

C₀₋₈ alkylene--NR³ --C₀₋₈ alkylene--O--;

A is selected from the group consisting of ##STR12## B is ##STR13## R¹,R², R³ and R⁴ are each independently selected from the group consistingof

hydrogen,

C₁₋₄ alkoxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

amino C₀₋₈ alkyl and

aryl C₀₋₈ alkyl;

R⁵ is selected from the group consisting of

hydrogen,

C₁₋₄ alkoxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

amino C₀₋₈ alkyl,

oxo and

aryl C₀ -₈ alkyl;

R⁶ and R⁷ are each independently selected from the group consisting of:

hydrogen,

C₀₋₆ alkylamino C₀₋₆ alkyl,

C₀₋₆ dialkylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkyloxycarbonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonylamino C₀₋₆ alkyl and

aryl C₀₋₆ alkylca:bonylamino C₀₋₆ alkyl;

R¹² is selected from the group consisting of

hydroxy,

C₁₋₈ alkyloxy,

C₁₋₆ dialkylaminocarbonylmethoxy and

aryl C₁₋₆ dialkylaminocarbonylrmethoxy; and

m and n are integers independently chosen from 0-6;

provided that when the compound is ##STR14## wherein R¹² is hydroxy orC₁₋₄ alkyloxy, then X-Y is not ##STR15## and the pharmaceuticallyacceptable salts thereof.

In a class of this embodiment is the compound wherein X is selected fromthe group consisting of ##STR16## Y is selected from the groupconsisting of C₁₋₂ alkylene, --C.tbd.C--,

C₀₋₂ alkylene--NH--CO--,

C₀₋₅ alkylene--O--C₀₋₁ alkylene and

--NH--C₂₋₄ alkylene--O--;

A is selected from the group consisting of ##STR17## R¹ is selected fromthe group consisting of hydrogen and

C₁₋₄ alkoxy;

R⁶ and R⁷ are each independently selected from the group consisting of

hydrogen,

--NHCbz,

--NHSO₂ Ph,

--NHC(O)--Ph and

--N(CH₃)--SO₂ Ph; and

m and n are integers independently chosen from 0-1.

Examples of this class are compounds selected from the group of:

4-(2-Guanidoethyloxy)phenylcarbonyl-2(S)-benzyloxycarbonylamino-βalanine,

4-(2-Guanidoethyloxy)phenylcarbonyl-2(S)-phenylsulfonylamino-βalanine,

2(S)-Phenylsulfonylamino-3- 4-(4-guanidobutyloxy)phenyl!-propionic acid,

2(S)-(N-Benzyloxycarbonylamino)-3-4-(5-guanidopentyloxy)phenyl!-propionic acid,

4-(3-Guanidinopropyloxy)benzoyl-2-(S)-phenylsulfonylamino-β-alanine,

4-(3-Formamidinopropyloxy)benzoyl-2-(S)-phenylsulfonylamino-βalanine,

3-Methoxy-4-(3-guanidinopropyloxy)benzoyl-2(S)-phenylsulfonyl-amino-β-alanine,

3-Methoxy-4-(3-aminopropyloxy)benzoyl-2(S)-phenylsulfonylamino-βalanine,

3-(3-Guanidinopropyloxy)benzoyl-2(S)-phenylsulfonylamino-βalanine,

4-2-(N-Phenylguanidino)ethyloxy!benzoyl-2(S)-phenylsulfonylaminoβ-alanine,

4-2-(N,N-Dimethylguanidino)ethyloxy!benzoyl-2(S)-phenylsulfonyl-amino.beta.-alanine,

4-(Guanidinophen-3-yloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(Guanidino)ethyloxymethyl!benzoyl-2(S)-phentylsulfonylamino-β-alanine,

3-2-(Guanidino)ethylaminocarbonyl!benzoyl-2(S)-phenylsulfonyl-amino-β-alanine,

4-2-(2-Aminothiazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester,

4-2-(2-Aminothiazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4- 2-(N-(2-Imidazolin-2-yl)aminoethyloxy!benzoyl-₂(S)-phenylsulfonyl-amino----alanine,

2(S)-Phenylsulfonylamino-3-4-(4-(N-imidazolin-2-yl)aminobutyloxy)-phenyl!propionic acid,

4- 2- N- Cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl!amino!-ethyloxybenzoyl-2(S)-phenylsulfonylamino β-alanine,

4-2-(Pyrimidin-2-ylamino)ethyioxy!benzoyl-2(S)-phenylsulfonylaminoβalanine,

4-2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4- 2-(₂-Aminothiazol-4-yl)ethyl!benzoyl-2(S)-phenyIsulfonylamino-β-alaninet-butyl ester,

4-2-(2-Aminothiazol-4-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-βalanine,

4- 2(S)-(N-(2-Imidazolin-2-yl)amino)propyloxy!benzoyl-2(S)-phenyl-sulfonylamino-β-alanine,

4- 2-(Imidazol-2-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-βalanine,

4-2-(Thiazol-2-ylamino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-βalanine,

4-2-(Pyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-benzyloxycarbonyl-amino-.beta.-alanine,

4-2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-benzyloxycarbonylamino-β-alanine,

Methyl 2(S)-benzoylamino-3-4-(4-pyrimidin-2-ylaminobutyloxy)phenyl!propionate,

2(S)-Benzoylamino-3- 4-(4-pyrimidin-2-ylamino)butyloxy)phenyl!propionicacid,

2(S)-Benzoylamino-3-4-(4-(3,4,5,6-tetrahydropyrimidin-2-ylamino)-butyloxy)phenyl!propionicacid,

4- 2-(Pyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-N-methyl-N-phenyl-sulfonylamino-β-alanine t-butyl ester,

4-2-(Pyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-N-methyl-N-phenyl-sulfonylamino-β-alanine,

4-2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-N-methyl-N-phenylsulfonylamino-β-alanine,

4-2-(N-(5,6-Dihydro-4-keto-1(H)-pyrimidin-2-yl)amino)ethyloxy!-benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonyl-amino-βalaninet-butyl ester,

4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonylamino-βalanine,

4-2-(2-Aminopyridin-6-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-βalanine,

4-2-(2-Aminopyridin-6-yl)ethyloxy!benzoyl-2(S)-phenyl-sulfonylamino-β-alaninet-butyl ester,

4-2-(2-Aminopyridin-6-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4- 2-(Indol-2-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninemethyl ester,

4- 2-(Indol-2-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4- 2-(1H-Imidazo4,5-6!pyridin2-yl)ethenyl!benzoyl-2(S)-phenyl-sulfonylamino-β-alaninet-butyl ester,

4- 2-(1H-Imidazo 4,5-b!pyridin-2-yl)ethenyl!benzoyl-2(S)-phenyl-sulfonylamino-β-alanine,

4- 2-(1H-Imidazo4,5-b!pyridin-2-yl)ethyl!benzoyl-2(S)-phenyl-sulfonylamino-β-alanine,

4-2-(1,8-Naphthyidin-7-yl)ethenyl)benzoyl-2(S)-phenylsulfonylaminoβ-alaninet-butylester,

4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester,

4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(1,8-Naphthyridin-7-yl)ethenyl!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alanineethyl ester,

4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanineethyl ester,

4-2-(1,2,3,4-Tetrahydro-1,8naphthyridin-7-yl)ethyl!benzoyl-2(S)1(S)10-camphorsulfonylamido!β-alanineethyl ester,

4-2-(1,2,3,4-Tetrahydro-1,8naphthyridin-7-yl)ethyl!benzoyl-2(S)-1(S)10-camphorsulfonylamido!β-aline,

4-(3-Aminoisoquinolin-1-yl)ethynyl!benzoyl-2(S)-phenylsulfonamido-β-alanineethyl ester,

4-(3-Aminoisoquinolin-1-yl)ethynyl!benzoyl-2(S)-phenylsulfonamido-β-alaninetrifluoroacetate,

4-2-(3-Aminoisoquinolin-1-yl)ethyl!benzoyl-2(S)-phenylsulfonamido-β-alaninetrifluoroacetate,

4- 3-N-(1H-Benzimidazo-2-yl)amino!propoxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester, and

4- 3-N-(1H-Benzimidazol-2-yl)amino!propoxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine.

Illustrative of the embodiment is a method of inhibiting the boneresorption activity of marranalian osteoclast cells comprising the stepof administering a pharmacologically effective amount of the compound.

A further illustration of the embodiment is a composition for inhibitingbone resorption activity of mammalian osteoclast cells comprising apharmacologically effective amount of the compound and apharmaceutically acceptable carrier.

Exemplifying the class is a method of inhibiting the bone resorptionactivity of mammalian osteoclast cells comprising the step ofadministering a pharmacologically effective amount of the compound.

Further exemplifying the class is a composition for inhibiting boneresorption activity of mammalian osteoclast cells comprising apharmacologically effective amount of the compound and apharmaceutically acceptable carder.

Also included within the scope of the invention is a method ofinhibiting the bone resorption activity of mammalian osteoclast cellscomprising the step of administering a pharmacologically effectiveamount of a compound of the formula:

    X-Y-Z-Aryl-A-B

wherein:

Aryl is a 6-membered aromatic ring containing 0, 1,2 or 3 N atoms andeither unsubstituted or substituted with one or more groups chosen fromR¹ and R² ;

X is selected from ##STR18## or a 4- to 10- membered mono- or polycyclicaromatic or nonaromatic ring system containing 0, 1, 2, 3 or 4heteroatoms selected from N, O and S and either unsubstituted orsubstituted with R¹³, R¹⁴, R¹⁵ or R¹⁶ ;

Y is selected from the group consisting of

C₀₋₈ alkylene,

C₃₋₁₀ cycloalkyl,

C₀₋₈ alkylene--NR³ --CO--C₀₋₈ alkylene,

C₀₋₈ alkylene--CONR³ --C₀₋₈ alkylene,

C₀₋₈ alkylene--O--C₀₋₈ alkylene,

C₀₋₈ alkylene--NR¹ --C₀₋₈ alkylene,

C₀₋₈ alkylene--S(O)_(0-2--C) ₀₋₈ alkylene,

C₀₋₈ alkylene--SO₂ --NR³ --C₀₋₈ alkylene,

C₀₋₈ alkylene--NR³ --SO₂ --C₀₋₈ alkylene,

C₀₋₈ alkylene--CO--C₀₋₈ alkylene,

(CH₂)₀₋₆ aryl(CH₂)₀₋₆,

(CH₂)₀₋₆ aryl--CO--(CH₂)₀₋₆,

(CH₂)₀₋₆ aryl--CO--NR³ --(CH₂)₀₋₆,

(CH₂)₀₋₆ arylNR³ CO(CH₂)₀₋₆ ##STR19## Z and A are each independentlyselected from the group consisting of ##STR20## where m and n areintegers independently chosen from 0-6; B is selected from ##STR21## R¹,R², R³ and R⁴ are each independently selected from the group consistingof

hydrogen,

halogen,

C₁₋₁₀ alkyl,

aryl C₀₋₈ alkyl,

amino C₀₋₈ alkyl,

C₁₋₃ acylamino C₀₋₈ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylarnino C₀₋₈ alkyl,

aryl C₀₋₆ alkylamino C₀₋₆ alkyl,

C₁₋₄ alkoxyamino C₀₋₈ alkyl,

hydroxy C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₄ alkoxy C₀₋₆ alkyl,

carboxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

carboxy C₀₋₆ alkyloxy,

hydroxy C₁₋₆ alkylamino C₀₋₆ alkyl,

hydroxy C₀₋₆ alkyl, ##STR22## R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are eachindependently selected from

hydrogen,

fluorine,

C₁₋₈ alkyl,

hydroxyl,

hydroxy C₁₋₆ alkyl,

carboxy C₀₋₆ alkyl,

C₁₋₆ alkyloxy,

C₁₋₆ alkylcarbonyl,

aryl C₀₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyloxy,

aryl C₀₋₆ alkylcarbonyloxy,

C₁₋₆ alkylaminocarbonyloxy,

C₃₋₈ cycloalkyl,

aryl C₀₋₆ alkyl,

C₀₋₆ alkylamino C₀₋₆ alkyl,

C₀₋₆ dialkylamino C₀₋₆ alkyl,

C₁₋₈ alkylsulfonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonylamino C₀₋₆ alkyl,

C₁₋₈ alkyloxycarbonylamino C₀₋₈ alkyl,

aryl C₀₋₈ alkyloxycarbonylamino C₀₋₈ alkyl,

C₁₋₈ alkylcarbonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylcarbonylamino C₀₋₆ alkyl,

C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl,

aryl C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl,

C₀₋₈ alkylaminosulfonylamino C₀₋₆ alkyl,

aryl C₀₋₈ alkylaminosulfonylamino C₀₋₆ alkyl,

C₁₋₆ alkylsulfonyl C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonyl C₀₋₆ alkyl,

C₁₋₆ alkylcarbonyl C₀₋₆ alkyl,

aryl C₀₋₆ alkylcarbonyl C₀₋₆ alkyl,

C₁₋₆ alkylthiocarbonylamino C₀₋₆ alkyl, and

aryl C₀₋₆ alkylthiocarbonylamino C₀₋₆ alkyl

wherein the alkyl, aryl, or N atoms may be unsubstituted or substitutedwith one or more substituents selected from R¹ and R² ;

R¹² is selected from

hydroxy,

C₁₋₈ alkyloxy,

aryl C₀₋₆ alkyloxy,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyloxy,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyloxy,

C₁₋₆ dialkylaminocarbonylmethyloxy,

aryl C₁₋₆ dialkylaminocarbonylmethyloxy or

an L- or D-amino acid joined by an amide linkage and

wherein the carboxylic acid moiety of said amino acid is as the freeacid or is esterified by C₁₋₆ alkyl; and

R³, R¹⁴, R¹⁵ and R¹⁶ are each independently selected from the groupconsisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl C₀₋₈ alkyl,

oxo,

thio,

amino C₀₋₈ alkyl,

C₁₋₃ acylamino C₀₋₈ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

aryl C₀₋₆ alkylamino C₀₋₆ alkyl,

C₁₋₄ alkoxyamino C₀₋₈ alkyl,

hydroxy C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₄ alkoxy C₀₋₆ alkyl,

carboxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

carboxy C₀₋₆ alkyloxy,

hydroxy C₁₋₆ alkylamino C₀₋₆ alkyl,

hydroxy C₀₋₆ alkyl, ##STR23## and the pharmaceutically acceptable saltsthereof.

In one embodiment of the method, compounds have the formula:

    X-Y-Z-Aryl-A-B

wherein:

Aryl is a 6-membered aromatic ting containing 0, 1,2 or 3 N atoms andeither unsubstituted or substituted with one or more groups chosen fromR¹ and R² ;

X is selected from ##STR24## or a 4- to 10- roeinhered mono- orpolycyclic aromatic or nonaromatic rig system containg 0, 1, 2, 3 or 4heteroatoms selected from N, O and S and either unsubstimted orsubstituted with R¹³, R¹⁴, R¹⁵ or R¹⁶ ;

Y is selected from the group consisting of

C₀₋₈ alkylene,

C₃₋₁₀ cycloalkyl,

C₀₋₈ alkylene--NR³ --CO--C₀₋₈ alkylene,

C₀₋₈ alkylene--CONR³ --C₀₋₈ alkylene,

C₀₋₈ alkylene--O--C₀₋₈ alkylene,

C₀₋₈ alkylene--NR¹ --C₀₋₈ alkylene,

C₀₋₈ alkylene--S(O)₀₋₂ --C₀₋₈ alkylene,

C₀₋₈ alkylene--SO₂ --NR³ --C₀₋₈ alkylene,

C₀₋₈ alkylene--NR³ --SO₂ --C₀₋₈ alkylene,

C₀₋₈ alkylene--CO--C₀₋₈ alkylene,

(CH₂)₀₋₆ aryl(CH₂)₀₋₆,

(CH₂)₀₋₆ aryl--CO--(CH₂)₀₋₆,

(CH₂)₀₋₆ aryloCO--NH--(CH₂)₀₋₆ and ##STR25## Z and A are eachindependently selected from the group consisting of ##STR26## where mand n are integers independently chosen from 0-6; B is selected from##STR27## R¹, R², R³ and R⁴ are each independently selected from thegroup consisting of

hydrogen,

halogen,

C₁₋₁₀ alkyl,

aryl C₀₋₈ alkyl,

amino C₀₋₈ alkyl,

C₁₋₃ acylamino C₀₋₈ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

aryl C₀₋₆ alkylamino C₀₋₆ alkyl,

C₁₋₄ alkoxyamino C₀₋₈ alkyl,

hydroxy C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₄ alkoxy C₀₋₆ alkyl,

carboxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

carboxy C₀₋₆ alkyloxy,

hydroxy C₁₋₆ alkylamino C₀₋₆ alkyl,

hydroxy C₀₋₆ alkyl, ##STR28## R⁶, R⁷, R⁸, R⁹, R¹⁰, and R¹¹ are eachindependently selected from

hydrogen,

fluorine,

C₁₋₈ alkyl,

hydroxyl,

hydroxy C₁₋₆ alkyl,

carboxy C₀₋₆ alkyl,

C₁₋₆ alkyloxy,

C₁₋₆ alkylcarbonyl,

aryl C₀₋₆ alkylcarbonyl,

C₁₋₆ alkylcarbonyloxy,

aryl C₀₋₆ alkylcarbonyloxy,

C₁₋₆ alkylaminocarbonyloxy,

C₃₋₈ cycloalkyl,

aryl C₀₋₆ alkyl,

C₀₋₆ alkylamino C₀₋₆ alkyl,

C₀₋₆ dialkylamino C₀₋₆ alkyl,

C₁₋₈ alkylsulfonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonylamino C₀₋₆ alkyl,

C₁₋₈ alkyloxycarbonylamino C₀₋₈ alkyl,

aryl C₀₋₈ alkyloxycarbonylamino C₀₋₈ alkyl,

C₁₋₈ alkylcarbonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylcarbonylamino C₀₋₆ alkyl,

C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl,

aryl C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl,

C₀₋₈ alkylaminosulfonylamino C₀₋₆ alkyl,

aryl C₀₋₈ alkylaminosulfonylamino C₀₋₆ alkyl,

C₁₋₆ alkylsulfonyl C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonyl C₀₋₆ alkyl,

C₁₋₆ alkylcarbonyl C₀₋₆ alkyl,

aryl C₀₋₆ alkylcarbonyl C₀₋₆ alkyl,

C₁₋ alkylthiocarbonylamino C₀₋₆ alkyl, and

aryl C₀₋₆ alkylthiocarbonylamino C₀₋₆ alkyl

wherein the alkyl or aryl groups may be unsubstituted or substitutedwith one or more substituents selected from R¹ and R² ;

R¹² is selected from

hydroxy,

C₁₋₈ alkyloxy,

aryl C₀₋₆ alkyloxy,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyloxy,

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyloxy,

C₁₋₆ dialkylaminocarbonylmethyloxy,

aryl C₁₋₆ dialkylaminocarbonylmethyloxy or

an L- or D-amino acid joined by an amide linkage and

wherein the carboxylic acid moiety of said amino acid is as the freeacid or is esterified by C₁₋₆ alkyl; and

R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently selected from the groupconsisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl C₀₋₈ alkyl,

oxo,

thio,

amino C₀₋₈ alkyl,

C₁₋₃ acylamino C₀₋₈ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

aryl C₀₋₆ alkylamino C₀₋₆ alkyl,

C₁₋₄ alkoxyamino C₀₋₈ alkyl,

hydroxy C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₄ alkoxy C₀₋₆ alkyl,

carboxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

carboxy C₀₋₆ alkyloxy,

hydroxy C₁₋₆ alkylamino C₀₋₆ alkyl,

hydroxy C₀₋₆ alkyl, ##STR29## and the pharmaceutically acceptable saltsthereof.

In a class of this embodiment, the compounds have the formula whereinAryl is a 6-membered aromatic ring containing 0, 1 or 2N atoms andeither unsubstituted or substituted with one or more groups chosen fromR¹ and R² ;

X is defined as above;

Y is selected from

C₀₋₈ alkylene,

C₀₋₈ alkylene--NR³ --CO--C₀₋₈ alkylene,

C₀₋₈ alkylene--CONR³ --C₀₋₈ alkylene,

C₀₋₈ alkylene--O--C₀₋₈ alkylene,

C₀₋₈ alkylene--NR¹ --C₀₋₈ alkylene,

C₀₋₈ alkylene--S(O)₀₋₂ --C₀₋₈ alkylene,

C₀₋₈ alkylene--SO₂ --NR³ --C₀₋₈ alkylene, or

C₀₋₆ alkylene--aryl--C₀₋₆ alkylene;

Z and A are each independently selected from the group consisting of##STR30## wherein m and n are independently chosen from 0-6; B isdefined as above;

R¹, R², R³ and R⁴ are each independently selected from

hydrogen,

C₁₋₁₀ alkyl,

aryl C₀₋₈ alkyl,

amino C₀₋₈ alkyl,

C₁₋₃ acylamino C₀₋₈ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

C₁₋₄ alkyloxy C₀₋₆ alkyl,

carboxy C₀₋₆ alkyl,

C₁₋₄ alkyloxycarbonyl C₀₋₆ alkyl,

carboxy C₀₋₆ alkyloxy,

hydroxy C₀₋₆ alkyl, ##STR31## R⁶, R⁷, R⁸, R⁹, R¹⁰ and R¹¹ areindependently selected from the group consisting of

hydrogen,

hydroxyl,

fluorine,

C₁₋₈ alkyl,

C₃₋₈ cycloalkyl,

aryl C₀₋₆ alkyl,

C₀₋₆ alkylamino C₀₋₆ alkyl,

C₀₋₆ dialkylamino C₀₋₆ alkyl,

C₁₋₈ alkylsulfonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonylamino C₀₋₆ alkyl,

C₁₋₈ alkyloxycarbonylamino C₀₋₈ alkyl,

aryl C₀₋₈ alkyloxycarbonylamino C₀₋₈ alkyl,

C₁₋₈ alkylcarbonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylcarbonylamino C₀₋₆ alkyl,

C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl,

aryl C₀₋₈ alkylaminocarbonylamino C₀₋₆ alkyl,

C₀₋₈ alkylaminosulfonylamino C₀₋₆ alkyl,

aryl C₀₋₈ alkylaminosulfonylamino C₀₋₆ alkyl,

C₁₋₆ alkylsulfonyl C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonyl C₀₋₆ alkyl,

C₁₋₆ alkylcarbonyl C₀₋₆ alkyl, and

aryl C₀₋₆ alkylcarbonyl C₀₋₆ alkyl;

R¹² is selected from the group consisting of

hydroxy,

C₁₋₈ alkyloxy,

aryl C₀₋₆ alkyloxy,

C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyloxy, and

aryl C₁₋₈ alkylcarbonyloxy C₁₋₄ alkyloxy; and

R¹³, R¹⁴, R¹⁵ and R¹⁶ are each independently selected from

hydrogen,

C₁₋₁₀ alkyl,

aryl C₀₋₈ alkyl,

oxo,

amino C₀₋₈ alkyl,

C₁₋₃ acylamino C₀₋₈ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

C₁₋₄ alkyloxy C₀₋₆ alkyl,

carboxy C₀₋₆ alkyl,

C₁₋₄ alkyloxycarbonyl C₀₋₆ alkyl,

carboxy C₀₋₆ alkyloxy,

hydroxy C₀₋₆ alkyl, ##STR32##

In a subclass of the class is the method wherein the compound has theformula: ##STR33## wherein: X is selected from the group consisting of##STR34## or a 5- to 10- membered aromatic or nonaromatic ring systemcontaining 0, 1, 2, 3 or 4 heteroatoms selected from N and S and eithertinsubstituted or substituted with R¹³, R¹⁴, R¹⁵ or R¹⁶ ;

Y is selected from the group consisting of

C₀₋₈ alkylene,

C₀₋₈ alkylene--NR³ --CO--C₀₋₈ alkylene,

C₀₋₈ alkylene--CONR³ --C₀₋₈ alkylene,

C₀₋₈ alkylene--O--C₀₋₈ alkylene,

C₀₋₈ alkylene--NR¹ --C₀₋₈ alkylene and

C₀₋₈ alkylene--S(O)₀₋₂ --C₀₋₈ alkylene;

Z and A are each independently selected from the group consisting of##STR35## wherein m and n are independently chosen from 0-6; B isdefined as above;

R¹, R², R³ or R⁴, are each independently selected from the groupconsisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl C₀₋₈ alkyl,

C₁₋₄ alkyloxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

carboxy C₀₋₆ alkyl,

hydroxy C₀₋₆ alkyl,

amino C₀₋₈ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl, ##STR36## R¹³, R¹⁴, R¹⁵ or R¹⁶, are eachindependently selected from the group consisting of

hydrogen,

C₁₋₁₀ alkyl,

aryl C₀₋₈ alkyl,

oxo,

C₁₋₄ alkyloxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

carboxy C₀₋₆ alkyl,

hydroxy C₀₋₆ alkyl,

amino C₀₋₈ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl, ##STR37##

In a group of this subclass is a method wherein X of the compound isselected from the group consisting of ##STR38## Y is selected from thegroup consisting of C₀₋₈ alkylene,

C₀₋₈ alkylene--NR³ --CO--C₀₋₈ alkylene,

C₀₋₈ alkylene--O--C₀₋₈ alkylene and

C₀₋₈ alkylene--NR¹ --C₀₋₈ alkylene;

Z and A are each independently selected from the group consisting of##STR39## wherein m and n are independently chosen from 0-6; B is##STR40## R¹, R², R³ and R⁴ are each independently selected from thegroup consisting of

hydrogen,

C₁₋₄ alkoxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

amino C₀₋₈ alkyl and

aryl C₀₋₈ alkyl;

R⁶ and R⁷ are each independently selected from the group consisting of:

hydrogen,

C₀₋₆ alkylamino C₀₋₆ alkyl,

C₀₋₆ dialkylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkyloxycarbonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonylamino C₀₋₆ alkyl and

aryl C₀₋₆ alkylcarbonylarnino C₀₋₆ alkyl;

R¹² is selected from the group consisting of

hydroxy and

C₁₋₈ alkyloxy; and

R¹³ is selected from the group consisting of

hydrogen,

C₁₋₄ alkoxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

amino C₀₋₈ alkyl,

oxo and

aryl C₀₋₈ alkyl.

In a subgroup of this group is a method wherein X of the compound isselected from the group consisting of ##STR41## Y is selected from thegroup consisting of C₀₋₂ alkylene,

C₀₋₂ alkylene--NH--CO--,

C₀₋₅ alkylene--O--C₀₋₁ alkylene and

--NH--C₂₋₄ alkylene;

R⁶ and R⁷ are each independently selected from the group consisting of

hydrogen,

--NHCbz,

--NHSO₂ Ph,

--NHC(O)--Ph, and

--N(CH₃)--SO₂ Ph.

Exemplifying the subgroup is the method wherein the compound is selectedfrom the group consisting of:

4-(2-Guanidinoethyloxy)benzoyl-2(S)-benzyloxycarbonylamino-β-alanine,

4-(2-Guanidinoethyloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine,

2-Phenylsulfonylamino-3- 4-(4-Guanidinobutyloxy)phenyl!-propionic acid,

2-(N-Benzyloxycarbonylamino)-3- 4-(5-guanidopentyloxy)phenyl!-propionicacid,

4(3-Guanidinopropyloxy)benzoyl-2-(S)-phenylsulfonylamino-β-alanine,

4(3-Formamidinopropyloxy)benzoyl-2-(S)-phenylsulfonylamino-β-alanine,

3-Methoxy-4-(3-Guanidinopropyloxy)benzoy-2(S)-phenylsulfonyl-amino-β-alanine,

3-Methoxy-4-(3-aminopropyloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine,

3(3-Guanidinopropyloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(N-Phenylguanidino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(N,N-Dimethylguanidino)ethyloxy!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alanine,

4-(Guanidinophen-3-yloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(Guanidino)ethyloxymethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

3-2-(Guanidino)ethylaminocarbonyl!benzoyl-2(S)-phenylsulfonyl-amino-β-alanine,

4-2-(1-Benzylimidazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alanine,

4- 2-(Imidazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(2-Aminothiazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester,

4-2-(2-Aminothiazol-4-yl)ethyloxy!benzoyl-2(S)-phtenylsulfonyl-amino-.beta.-alanine,

4-2-(N-(2-Imidazolin-2-yl)aminoethyloxy!benzoyl-2(S)-phenylsulfonylamino-.beta.-alanine,

2(S)-Phenylsulfonylamino3-4-(4-(N-imidazolin-2yl)aminobutyloxy)-phenyl!propionic acid,

4- 2- N-Cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl!amino!-ethyloxybenzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(Pyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(2-Aminothiazol-4-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-βalaninet-butyl ester,

4-2-(2-Aminothiazol-4-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-(S)-(N-(2-Imidazolin-2-yl)amino)propyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4- 2-(Imidazol-2-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(Thiazol-2-ylamino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(Pyrimidin-ylamino)ethyloxy!benzoyl-2(S)-benzyloxycarbonyl-amino-.beta.-alanine,

4- 2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-benzyloxycarbonylamino-β-alanine,

Methyl 2(S)-benzoylamino-3-4-(4-pyrimidin-ylaminobutyloxy)phenyl!propionate,

2(S)-Benzoylamino3- 4-(4-pyrimidin-2-ylamino)butyloxy)phenyl!-propionicacid,

2(S)-Benzoylamino-3-4-(4-(3,4,5,6-tetrahydropyrimidin-2-ylamino)-butyloxy)phenyl!-propionicacid,

4-2-(Pyrimidin-ylamino)ethyloxy!benzoyl-2(S)-N-methyl-N-phenyl-sulfonylamino-β-alaninet-butyl ester,

4-2-(Pyrimidin-ylamino)ethyloxy!benzoyl-2(S)-N-methyl-N-phenyl-sulfonylamino-β-alanine,

4- 2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-N-methyl-N-phenylsulfonylamino-β-alanine,

4- 2-(N-(5,6-Dihydro-keto-1(H)-pyrimidin-2yl)amino)ethyloxy!-benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonyl-amino-β-alaninet-butyl ester,

4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(2-Aminopyridin-6-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(2-Aminopyridin-6-yl)ethyloxy!benzoyl-2(S)-phenyl-sulfonylamino-β-alaninet-butyl ester,

4-2-(2-Aminopyridin-6-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(Indol-2-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninemethylester, and

4- 2-(Indol-2-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-βp-alanine.

In another embodiment of the method of the invention, X of the compoundis ##STR42## Y is selected from the group consisting of C₀₋₈ alkylene,

C₀₋₈ alkylene--NR³ --CO--C₀₋₈ alkylene,

C₀₋₈ alkylene--O--C₀₋₈ alkylene and

C₀₋₈ alkylene--NR¹ --C₀₋₈ alkylene;

Z and A are each independently selected from the group consisting of##STR43## wherein m and n are independently chosen from 0-6; B is##STR44## R¹¹, R², R³ and R⁴ are each independently selected from thegroup consisting of

hydrogen,

C₁₋₄ alkoxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

amino C₀₋₈ alkyl and

aryl C₀₋₈ alkyl;

R⁶ and R⁷ are each independently selected from the group consisting of:

hydrogen,

C₀₋₆ alkylamino C₀₋₆ alkyl,

C₀₋₆ dialkylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkyloxycarbonylamino C₀₋₆ alkyl,

aryl C₀₋₆ alkylsulfonylamino C₀₋₆ alkyl and

aryl C₀₋₆ alkylcarbonylamino C₀₋₆ alkyl;

R¹² is selected from the group consisting of

hydroxy and

C₁₋₈ alkyloxy; and

R¹³ is selected from the group consisting of

hydrogen,

C₁₋₄ alkoxy C₀₋₆ alkyl,

C₁₋₄ alkoxycarbonyl C₀₋₆ alkyl,

C₁₋₆ alkylamino C₀₋₈ alkyl,

C₁₋₆ dialkylamino C₀₋₈ alkyl,

amino C₀₋₈ alkyl,

oxo and

aryl C₀₋₈ alkyl.

In a class of this embodiment, X of the compound is selected from##STR45## A and B are defined as above; Y is selected from the groupconsisting of

C₀₋₂ alkylene,

C₀₋₂ alkylene--NH--CO--,

C₀₋₅ alkylene--O--C₀₋₁ alkylene and

--NH--C₂₋₄ alkylene;

R⁶ and R⁷ are each independently selected from the group consisting of

hydrogen,

--NHCbz,

--NHSOPh,

--NHC(O)--Ph, and

--N(CH₃)--SO₂ Ph.

Exemplifying the class is a method wherein the compound is selected fromthe group consisting of

4- 2-(1H-Imidazo4,5-6!pyridin-2-yl)ethenyl!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester,

4- 2-(1H-Imidazo4,5-b!pyridin--yl)ethenyl!benzoyl-2(S)-phenyl-sulfonylamino-β-alanine,

4- 2-(1H-Imidazo4,5-b!pyridin--yl)ethyl!benzoyl-2(S)-phenyl-sulfonylamino-β-alanine,

4-2-(1,8-Naphthyidin-7-yl)ethenyl)benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butylester,

4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester,

4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine,

4-2-(1,8-Naphthyridin-7-yl)ethenyl!benzoyl-2(S)-phenylsulfonyl-β-amino-alanineethyl ester,

4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanineethyl ester,

4- 2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)1(S)10-camphorsulfonylamido!β-alanine

4- 2-(1,2,3,4-Tetrahydro-1,8 naphthyridin-7-yl)ethyl!benzoyl-2(S)1(S)10-camphorsulfonylamido!β-alanine,

4-(3-Aminoisoquinolin-1-yl)ethynyl!benzoyl2(S)-phenylsulfonamido-β-alanineethyl ester,

4-3-(3-Aminoisoquinolin-1-yl)ethynyl!benzoyl-2(S)-phenylsulfonamido-β-alaninetrifluoroacetate,

4-2-(3-Aminoisoquinolin-1-yl)ethyl!benzoyl-2(S)-phenylsulfonamido-β-alaninetrifluoroacetate,

4- 3-N-(1H-Benzimidazo-2-yl)amino!propoxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester, and

4- 3-N-(1H-Benzimidazol-2-yl)amino!propoxy!benzoyl-21(S)-phenylsulfonylamino-β-alanine.

DETAILED DESCRIPTION OF THE INVENTION

Compounds of the invention are useful for treating mammals sufferingfrom a bone condition caused or mediated by increased bone resorption,who are in need of such therapy. Pharmacologically effective amounts ofthe compounds, including phararnaceutically acceptable salts thereof,are administered to the mammal, to inhibit the activity of mammalianosteoclasts.

Compounds of the invention are also useful for inhibiting tumor growthin mammals. Pharmacologicaly effective amounts of the compounds,including pharamaceutically acceptable salts thereof, are administeredto the mammal, to inhibit tumor growth. The growth of tumors depends onan adequate blood supply, which in turn depends on growth of new vesselsinto the tumor. New vessels are stimulated by factors secreted by thetumor. Inhibition of angiogenesis can cause tumor regression in animals.

Compounds of the invention are also useful for treating and preventingdiabetic retinopathy in mammals. Pharmacologically effective amounts ofthe compounds, including pharamaceutically acceptable salts thereof, areadministered to the mammal, to inhibit diabetic retinopathy.

Compounds are also useful in the prevention of restenosis of vessels.

The term "pharmaceutically acceptable salts" means non-toxic salts ofthe compounds of this invention which are generally prepared by reactingthe free base with a suitable organic or inorganic acid. Representativesalts include the following salts: Acetate, benzene-sulfonate, benzoate,bicarbonate, bisulfate, bitanrate, borate, bromide, calcium edetate,camsylate, carbonate, chloride, clavulanate, citrate, dihydrochloride,edetate, edisylate, estolate, esylate, fumarate, glucoheptanate,gluconate, glutamate, glycollylarsanilate, hexylresor-cinate,hydrabamine, hydrobromide, hydrochloride, hydroxynapthoate, iodide,isothionate, lactate, lactobionate, laurate, malate, maleate, mandelate,mesylate, methylbromide, methylnitrate, methylsulfate, mucate,napsylate, nitrate, oleate, oxalate, pamaote, palmitate, pantothenate,phosphate/diphosphate, polygalactouronate, salicylate, stearate,subacetate, succinate, tannate, tartrate, teoclate, tosylate,tfiethiodide, valerate. The term also includes acid salts of thecompounds, e.g., sodium salts, potassium salts, magnesium salts, etc.

The term "pharmaceutically effective amount" means that amount of a drugor pharmaceutical agent that will elicit the biological or medicalresponse that is being sought by a researcher or clinician.

The term "aryl" means a mono- or polycyclic system composed of 5- and/or6- membered aromatic tings containing 0, 1, 2, 3, or 4 heteroatomschosen from N, O or S and either unsubstituded or substituted. "aryl"with a lower case "a" is defined herein to be broader than the term"Aryl" with a capital "A". One skilled in the art can readilydistinguish between the two terms which are clearly defined herein.

The term "bone resorption activity" means the process by whichosteoclasts solubilize bone minerals and increase the activity ofenzymes that degrade bone matrix.

The term "alkyl" means straight, branched, or cyclic alkane, alkene oralkyne.

The term "alkylene" shall include both straight and branched chainalkylenes (e.g.,-CH₂ -,-CH(CH₃)-,-CH(CH₃)-CH₂ -, etc.).

The term "alkoxy" includes an alkyl portion where alkyl is as definedabove.

The terms "arylalkyl" and "alkylaryl" include an alkyl portion wherealkyl is as defined above and an aryl portion where aryl is as definedabove. The C_(0-n) or C_(1-n) designation where n may be an integerfrom1-10 or 2-10 respectively, refers to the alkyl component of thearylalkyl or alkylaryl unit.

The term "halogen" includes fluorine, chlorine, iodine and bromine. Theterm "oxy" means an oxygen (O) atom. The term "oxo" refers to a bivalentoxygen atom (═O). The term "thio" shall mean a sulfur (S) atom. In theschemes and examples below, various reagent symbols have the followingmeanings:

The term "L- or D-amino acids" means naturally occurring L- or D-aminoacids, for example, those naturally occurring L-amino acids present inhumans, e.g. protein amino acids, including L-alanine, L-arginine,L-asparagine, L-aspartic acid, L-cysteine, L-glutamine, L-glutamic acid,L-glycine, L-histidine, L-isoleucine, L-leucine, L-lysine, L-methionine,L-phenylalanine, L-proline, L-serine, L-threonine, L-tryptophan,L-tyrosine, and L-valine, and those naturally occurring D-amino acidswhich are non-protein amino acids, such as those found, for example, inantibiotic substances produced by bacteria and fungi, includingD-valine, D-asparagine, D-glutamate, D-ornithine, D-phenylalanine,D-leucine, D-cysteine, and D.-aspartate. (see Zubay "BIOCHEMISTRY"Addison-Wesley Publishing Company, Inc. (Reading, Me.) 1983 pp. 867-870and Stryer ."BIOCHEMISTRY" W. H. Freeman and Company (New York, N.Y.)3rd Edition 1988 pp. 16-21).

BOC(Boc): t-butyloxycarbonyl.

Pd/C: Palladium on activated carbon catalyst.

DMF: Dimethylformamide.

DMSO: Dimethylsulfoxide.

CBZ(Cbz): Carbobenzyloxy or benzyloxycarbonyl.

CHC₂ Cl₂ : Methylene chloride.

CHCl₃ : Chloroform.

EtOH: Ethanol.

NMM: N-methylmorpholine

CDI: Carbonyldiimidazole

HOBT: 1-Hydroxybenzotriazole

MeOH: Methanol.

EtOAc: Ethyl acetate.

HOAc: Acetic acid.

BOP: Benzotriazol-1-yloxytris(dimethylamino)phosphoniumhexafluorophosphate.

DPFN: 3,5-Dimethyl-1-pyrazolylformamidine nitrate

BH₃ ·DMS: Borane·dimethylsulfide

EDC: 1-(3-Dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride

LDA: Lithium diisopropylamide

DME: 1,2-Dimethoxyethane

DEAD: Diethyl azodicarboxylate

Dibal: Diisobutylaluminum hydride

THF: Tetrahydrofuran

TEA: Triethylamine

TFA: Trifluoroacetic acid

DIPEA: Diisopropylethylamine

DIAD: Diisopropyl azodicarboxylate

PCA·HCI: Pyrazole carboxamidine hydrochloride

The compounds of the present invention can be administered in such oraldosage forms as tablets, capsules (each of which includes sustainedrelease or timed release formulations), pills, powders, granules,elixers, tinctures, suspensions, syrups and emulsions. Likewise, theymay also be administered in intravenous (bolus or infusion),intraperitoneal, subcutaneous or intramuscular form, all using formswell known to those of ordinary skill in the pharmaceutical arts.

The dosage regimen utilizing the compounds of the present invention isselected in accordance with a variety of factors including type,species, age, weight, sex and medical condition of the patient; theseverity of the condition to be treated; the route of administration,the renal and hepatic function of the patient; and the particularcompound or salt thereof employed. An ordinarily skilled physician orveterinarian can readily determine and prescribe the effective amount ofthe drug required to prevent, counter or arrest the progress of thecondition.

Oral dosages of the present invention, when used for the indicatedeffects, will range between about 0.01 mg per kg of body weight per day(mg/kg/day) to about 100 mg/kg/day and preferably 1.0-100 mg/kg/day andmost preferably 1.0 to 20 mg/kg/day. Intravenously, the most preferreddoses will range from about 0.1 to about 10 mg/kg/minute during aconstant rate infusion. Advantageously, compounds of the presentinvention may be administered in a single daily dose, or the total dailydosage may be administered in divided doses of two, three or four timesdaily. Furthermore, preferred compounds for the present invention can beadministered in intranasal form via topical use of suitable intranasalvehicles, or via transdermal routes, using those forms of transdermalskin patches well known to those of ordinary skill in the art. To beadministered in the form of a transdermal delivery system, the dosageadministration will, of course, be continuous rather than intermittantthroughout the dosage regimen.

In the methods of the present invention, the compounds herein describedin detail can form the active ingredient, and are typically administeredin admixture with suitable pharmaceutical diluents, excipients orcarriers (collectively referred to herein as `carrier` materials)suitably selected with respect to the intended form of administration,that is, oral tablets, capsules, elixirs, syrups and the like, andconsistent with conventional pharmaceutical practices.

For instance, for oral administration in the form of a tablet orcapsule, the active drug component can be combined with an oral,non-toxic, pharmaceutically acceptable, inert carrier such as lactose,starch, sucrose, glucose, methyl cellulose, magnesium stearate,dicalcium phosphate, calcium sulfate, mannitol, sorbitol and the like;for oral administration in liquid form, the oral drug components can becombined with any oral, non-toxic, pharmaceutically acceptable inertcarrier such as ethanol, glycerol, water and the like. Moreover, whendesired or necessary, suitable binders, lubricants, disintegratingagents and coloring agents can also be incorporated into the mixture.Suitable binders include starch, gelatin, natural sugars such as glucoseor beta-lactose, corn sweeteners, natural and synthetic gums such asacacia, tragacanth or sodium alginate, carboxymethylcellulose,polyethylene glycol, waxes and the like. Lubricants used in these dosageforms include sodium oleate, sodium stearate, magnesium stearate, sodiumbenzoate, sodium acetate, sodium chloride and the like. Disintegratorsinclude, without limitation, starch, methyl cellulose, agar, bentonire,xanthan gum and the like.

The compounds of the present invention can also be administered in theform of liposome delivery systems, such as small unilamellar vesicles,large unilamellar vesicles and multilamellar vesicles. Liposomes can beformed from a variety of phospholipids, such as cholesterol,stearylamine or phosphatidylcholines.

Compounds of the present invention may also be delivered by the use ofmonoclonal antibodies as individual carriers to which the compoundmolecules are coupled. The compounds of the present invention may alsobe coupled with soluble polymers as targetable drug carriers. Suchpolymers can include polyvinylpyrrolidone, pyran copolymer,polyhydroxypropylmethacrylamide-phenol,polyhydroxyethylaspartamide-phenol, or polyethyleneoxide-polylysinesubstituted with palmitoyl residues. Furthermore, the compounds of thepresent invention may be coupled to a class of biodegradable polymersuseful in achieving controlled release of a drug, for example,polylactic acid, polyglycolic acid, copolymers of polylactic andpolyglycolic acid, polyepsilon caprolactone, polyhydroxy butyric acid,polyorthoesters, polyacetals, polydihydropyrans, polycyanoacrylates andcrosslinked or amphipathic block copolymers of hydrogels.

The novel compounds of the present invention were prepared according tothe procedure of the following schemes and examples, using appropriatematerials and are further exemplified by the following specificexamples. The most preferred compounds of the invention are any or allof those specifically set forth in these examples. These compounds arenot, however, to be construed as forming the only genus that isconsidered as the invention, and any combination of the compounds ortheir moieties may itself form a genus. The following examples furtherillustrate details for the preparation of the compounds of the presentinvention. Those skilled in the an will readily understand that knownvariations of the conditions and processes of the following preparativeprocedures can be used to prepare these compounds. All temperatures aredegrees Celsius unless otherwise noted. ##STR46## Methyl4-(2-N-BOC-Aminoethyloxy)benzoate (1-3).

To a stirred solution of 1-2 (1.6 g, 10.5 mmol; Aldrich), PPh3 (3.4 g,13.1 mmol), and THF (38 mL) at ambient temperature, was added 1-1 (1.7g, 10.5 mmol) and DEAD (5.1 mL, 11.0 mmol; 40% toluene solution) in THF(15 mL) dropwise over a 15 min period. After stirring for 20 h thereaction mixture was diluted with EtOAc and then washed with sat.NaHCO₃, 10% KHSO₄ and brine, dried (MgSO4) and concentrated. Flashchromatography (silica, 20% EtOAc/hexanes) gave 1-3 as a colorless oil.Rf 0.84 (silica, 30% EtOAc/hexanes).

¹ H NMR (300 MHz, CDCl₃) δ 8.02 (d, 2H), 6.93 (d, 2H), 5.02 (m, 1H),4.11 (m, 2H), 3.89 (s, 3H), 3.58 (m, 2H), 1.46 (s, 9H).

4- 2-(N-BOC-Amino)ethyloxy!benzoic acid (1-4)

A mixture of 1-3 (1.3 g, 4.4 mmol), 1N NaOH (26.7 mL, 26.7 mmol) andethanol (33 mL) was stirred at ambient temperature for 20 h. Thereaction mixture was concentrated and the residue dissolved in H₂ O (15mL) and then washed with ether. The aqueous portion was acidified with10% KHSO₄ and then extracted with EtOAc. The organic phase was washedwith brine, dried (MgSO₄) and concentrated to give 1-4 as a white solid.Rf 0.26 (silica, 9:1:1 CH₂ Cl₂ /CH₃ OH/AcOH).

¹ H NMR (300 MHz, CDCl₃) δ 8.08 (d, J=9 Hz, 2H), 6.96 (d, J=9 Hz, 2H),5.02 (m, 1H), 4.12 (m, 2H), 3.60 (m, 2H), 1.48 (s, 9H).

4- 2-(N-BOC-Amino)ethyloxy!benzoyl-2(S)-benzyloxycarbonylaminoβ-alaninemethyl ester (1-6)

To a stirred solution of 1-4 (1.1 g, 4.1 mmol), 1-5 (0.97 g, 4.1 mmol)HOBT (0.55 g, 4.1 mmol), N(i-Pr)₂ Et (2.2 mL, 12.3 mmol), and DMF (45mL) at -15° C. was added EDC (0.81 g, 4.1 mmol) followed by removal ofthe cooling bath. After 72 h the reaction mixture was diluted with EtOAcand then washed with H₂ O, sat. NaHCO₃, 10% KHSO₄ and brine, dried(MgSO₄) and concentrated. Flash chromatography (silica, 70%EtOAc/hexanes) gave 1-6 as a white powder. Rf 0.64 (silica, EtOAc).

¹ H NMR (300 MHz, CDCl₃) δ 7.72 (d, J=9 Hz, 2H), 7.34 (m, 5H), 6.91 (d,J=9 Hz, 2H), 6.80 (m, 1H), 5.95 (m, 1H), 5.13 (m, 2H), 4.99 (m, 1H),4.55 (m, 1H), 4.08 (m, 2H), 3.85 (m, 2H), 3.80 (s, 3H), 3.56 (m, 2H),1.47 (s, 9H).

4- 2-(N-BOC-Amino)ethyloxy!benzoyl-2(S)-benzyloxycarbonylaminoβ-alanine(1-7)

Utilizing the procedure for converting 1-3 to 1-4, 1-6 (300 mg, 0.64mmol) gave 1-7 as a colorless oil. Rf 0.59 (silica, 9:1:1 CH₂ Cl₂ /CH₃OH/AcOH).

¹ H NMR (300 MHz, CDCl₃) δ 7.70 (d, 2H), 7.30 (m, 5H), 6.80 (d, 2H),6.52 (m, 1H), 5.12 (m, 1H), 5.06 (m, 2H), 4.39 (m, 1H), 4.00-3.50 (m,6H), 1.46 (s, 9H).

4- 2-(Guanido)ethyloxy!benzoyl-2(S)-benzyloxycarbonylamino-palaninc(1-8)

A solution of 1-7 (210 mg, 0.46 mmol), CH₂ Cl₂ (3 mL) and TFA (3 mL) wasstirred at ambient temperature for 30 min followed by concentration.Most of the excess TFA was then removed azeotropically with toluene. Theresulting oil was dissolved in DMF/H₂ O (4 mL; 3:1), treated with DIPEA(0.36 mL, 2.5 mmol) and DPFN (0.12 g, 0.65 mmol) and then heated at 60°C. for 2 h. The cooled reaction mixture was concentrated and theresidual H₂ O removed with an ethanol azeotrope. Flash chromatography(silica, 10:0.8:0.8 ethanol/NH₄ OH/H₂ O) gave 1-8 as a white powder. Rf0.25 (silica, 10:1:1 ethanol/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, CD₃ OD) δ 7.53 (d, J=9 Hz, 2H), 7.06 (m, 5H), 6.74 (d,J=9 Hz, 2H), 4.81 (m, 2H), 4.03 (m, 1H), 3.94 (t, J=5 Hz, 2H), 3.48 (m,2H), 3.36 (t, J=5 Hz, 2H). ##STR47## Methyl3-amino-2(S)-benzyloxycarbonylaminopropionate hydrochloride (1-5)

3-Amino-2(S)-benzyloxycarbonylaminopropionic acid (Fluka) (5.0 g, 21.0mmoles) was suspended in MeOH and at -10°SOCl₂ (23.0 mmoles) was added.The reaction mixture was allowed to gradually warm to room temperatureover 16 h. The solvent was then removed and the resulting solid wastriturated with Et₂ O to give 1-5.

¹ H NMR (300 MHz, D₂ O) δ 3.32 (2H, m), 3.52 (2H, m), 3.70 (1H, m), 3.80(4H, m), 4.59 (1H, m), 5,18 (3H, s), 7.45 (5H, s). ##STR48## tert-Butyl3-amino-2(S)-phenylsulfonylaminopropionate hydrochloride 2-1)

In a Fischer-Porter tube, a mixture of 2-1b (10.2 g, 42 mmol) and DME(150 mL) was sequentially treated with H₂ SO₄ (6.4 mL, 0.12 mol), cooledto -78° C., and then condensed isobutylene (75 mL). The cooling bath wasremoved. After 24 h, ice/water (250 mL) was added followed by washingwith ether (2x). The aqueous phase was basified with aq 6N NaOH, thensaturated with NaCl, followed by extraction with EtOAc (3x). Thecombined extracts were washed with brine, dried (MgSO₄), andconcentrated to give a white solid. This was dissolved in CH₂ Cl₂ andtreated with 1N HCl/ether (22 mL), and then concentrated to give 2-1 asa glassy yellow solid.

¹ H NMR (400 MHz, DMSO) δ 8.25-8.00 (m, 4H), 7.85-7.58 (m, 5H), 4.08 (m,1H), 3.10 (m, 1H), 2.73 (m, 1H), 1.17 (s, 9H).

4 - 2 -(N -BOC-Amino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-βalaninetert-butyl ester (2-3)

To a stirred solution of 1-4 (200 mg, 0.71 mmol), 2-1 (260 mg, 0.85mmol), NMM (313 μL, 2.8 mmol), and CH₃ CN (4 mL) at ambient temperaturewas added BOP reagent (473 mg, 1.1 mmol). After 20 h the reactionmixture was diluted with EtOAc and then washed with H₂ O, sat. NaHCO₃,10% KHSO₄ and brine, dried (MgSO₄) and concentrated. Flashchromatography (silica, 40% EtOAc/hexanes) gave 2-3 as a white solid. Rf0.19 (silica, 40% EtOAc/hexanes).

¹ H NMR (300 MHz, CD₃ OD) δ 7.77 (m, 2H), 7.67 (d, J=9 Hz, 2H), 7.42 (m,3H), 6.92 (d, J=9 Hz, 2H), 4.02 (m, 3H), 3.59 (dd, 1H), 3.42 (dd, 1H),3.38 (m, 2H), 1.38 (s, 9H), 1.16 (s, 9H).

4- 2-(Guanidino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine(2-4)

A solution of 2-3 (340 mg, 0.64 mmol), TFA (3 mL), and CH₂ Cl₂ (3 mL)was stirred at ambient temperature for 1.0 h. Concentration, followed byazeotropic removal of the residual TFA, with toluene, gave an oil whichwas dissolved in DMF/H₂ O (3 mL; 3:1) and then treated with N(i-Pr)₂Et(334 μL, 1.9 mmol) and DPFN (193 mg. 0.95 mmol). This solution washeated at 60° C. for 4 h and the cooled reaction mixture concentrated.Flash chromatography (silica, 10/0.2/0.2 to 10/1/1 ethanol/NH₄ OH/H₂ O)gave 2-4 as a white powder.

Rf0.20 (silica, 10/1/1 ethanol/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, D₂ O) δ 7.62 (m, 2H), 7.4.3 (d, J=9 Hz, 2H), 7.18 (m,3H), 6.93 (d, J=9 Hz, 2H), 4.18 (m, 2H), 3.72 (m, 1H), 3.55 (m, 3H),3.19 (m, 1H).

N-Phenylsulfonyl-L-asparagine (2-1a)

To a stirred solution of L-asparagine (Aldrich) (10 g, 76 mmol), NaOH(3.4 g, 85 mmol), H₂ O (50 mL), and dioxane (50 mL) at 0° C. was addedPhSO₂ Cl (10.6 mL, 84 mmol). After 1 min, NaOH (3.4 g) in H₂ O (50 mL)was added and the reaction mixture stirred for 30 MIN. The reactionmixture was then concentrated to remove dioxane then washed with EtOAc.The aqueous phase was then cooled to 0° C. and acidified to pH 5.0 withcone. HCI to effect product precipitation. The resulting solid wascollected by filtration, washed with H₂ O (20 mL) and dried at 50° C.under vacuum to give N-phenylsulfonyl-Lasparagine (2-1a) as a whitesolid.

Rf 0.40 (silica, 10:1:1 ethanol/H₂ O/NH₄ OH).

¹ H NMR (300 MHz, D₂ O) δ 7.59 (m, 2H), 7.26 (m, 3H), 3.92 (m, 1H), 3.02(m, 1H), 2.35 (m, 1H). ##STR49##3-Amino-2(S)-phenylsulfonylaminopropionic acid (2-1b)

To stirred solution of NaOH (15.6 g, 0.4. mol) in H₂ O (70 mL), cooledwith an icebath, was added bromine (3.6 mL, 0.07 mol) dropwise. After 5min, a cold solution of N-phenylsulfonyl-Lasparagine 2-1a (14.6 g, 54mmol) and NaOH (4.3 g, 0.1 mol) in H₂ O (50 mL) was added in oneportion. The solution was stirred for 20 min at 0° C. then 30 min at 90°C. The reaction mixture was recooled to 0° C., and the pH adjusted to 7through dropwise addition of cone. HCl. The white precipitate formed wascollected by filtration and then dried to give (2-1b) as a white solid.¹ H NMR (300 MHz, D₂ O) δ 8.00-7.50 (m, 5H), 3.88 (m, 1H), 3.37 (m, 1H),3.12 (m, 1H).

Methyl 3-Amino-2(S)-phenylsulfonylaminopropionate hydrochloride (2-2)

To a stirred solution of 2-1b (5.0 g, 21 mmol) in CH₃ OH (100 mL) at 0°C. was added SOCl₂ (7.5 mL, 100 mmol) dropwise. The cooling bath wasthen removed and the solution stirred at ambient temperature for 20 h.Concentration and trituration with ether gave 2-2 as a white solid.

¹ H NMR (300 MHz, D₂ O) δ 7.82-7.50 (m, 5H), 4.32 (m, 1H), 3.40 (m, 1H),3.32 (s, 3H), 3.10 (m, 1H).

tert-Butyl 3-amino-2(S)-phenylsulfonylaminopropionate hydrochloride(2-1)

In a Fischer-Porter tube, a mixture of 2-1b (10.2 g, 42 mmol) and DME(150 mL) was sequentially treated with H₂ SO₄ (6.4 mL, 0.12 mol), cooledto -78° C., and then condensed isobutylene (75 mL). The tube was sealedand the cooling bath was removed. After 24 h, ice/water (250 mL) wasadded followed by washing with ether (2x). The aqueous phase wasbasified with aq 6N NaOH, then saturated with NaCl, followed byextraction with EtOAc (3x). The combined extracts were washed withbrine, dried (MgSO₄), and concentrated to give a white solid. This wasdissolved in CH₂ Cl₂ and treated with 1N HCl ether (22 mL), and thenconcentrated to give 2-1as a glassy yellow solid.

¹ H NMR (400 MHz, DMSO) δ 8.25-8.00 (m, 4H), 7.85-7.58 (m, 5H), 4.08 (m,1H), 3.10 (m, 1H), 2.73 (m, 1H), 1.17 (s, 9H). ##STR50##

Methyl 3-amino-2(S)-benzyloxycarbonylaminopropionate hydrochloride (1-5)3-Amino-2(S)-benzyloxycarbonylaminopropionic acid (Fluka) (5.0 g, 21.0mmoles) was suspended in MeOH and at -10° C. SOCl₂ (1.7 mL, 23.0 mmoles)was added. The reaction mixture was allowed to gradually warm to roomtemperature over 16 h. The solvent was then removed and the resultingsolid was triturated with Et₂ O to give 1-5.

¹ H NMR (300 MHz, D₂ O) δ 7.45 (s, 5H), 5.18 (s, 3H), 4.59 (m, 1H), 3.80(m, 4H), 3.70 (m, 1H), 3.52 (m, 2H), 3.32 (m, 2H). ##STR51## Ethylimidazol-4-ylacetate (3-2)

To a suspension of 3-1 (5.0 g, 30.7 mmol, Aldrich) in ethanol (100 mL)at ambient temperature was added SOCl₂ (11.2 mL, 154 mmol) dropwise.After stirring overnight the homogenous solution was concentrated andthe residue suspended in CH₂ Cl₂ and washed with sat. NaHCO₃. The sat.NaHCO₃ was back-extracted with CH₂ Cl₂. The CH₂ Cl₂ portions werecombined, dried (MgSO₄), and concentrated to give 3-2 as a pale yellowliquid.

¹ H NMR (300 MHz, CDCl₃) δ 7.60 (s, 1H), 6.97 (s, 1H), 4.10 (q, 2H),3.67 (s, 2H), 1.24 (t, 3H).

Ethyl 1-Benzylimidazol-4-ylacetate (3-3)

A THF (15 mL) solution of 3-2 (3.8 g, 24.6 mmol), was added dropwise toa stirred suspension of NaH (1.1 g, 26.5 mmol) in THF (25 mL) at 0° C.over 30 min. The cooling bath was then removed and the mixture stirredat ambient temperature for 3 h followed by dropwise addition of benzylbromide (24.6 mmol) over 30 min. After 20 h the solvent was evaporatedand the residue partitioned between CH₂ Cl₂ and H₂ O. The organic phasewas washed with H₂ O, dried (MgSO₄), and concentrated. Flashchromatography (silica, 40% (CHCl₃ /NH₃)/EtOAc) gave 3-3 as a paleyellow oil. Rf 0.15 (silica, 40% (CHCl₃ /NH₃)/EtOAc)).

¹ H NMR (300 MHz, CDCl₃) δ 7.52 (s, 1H), 7.40-7.10 (m, 5H), 6.87 (s,1H), 5.08 (s, 2H), 4.15 (q, 2H), 3.62 (s, 2H), 1.26 (t, 3H).

2-(1-Benzylimidazol-4-yl)ethanol (3-4)

To a stirred solution of 3-3 (4.6 g, 19 mmol) in THF (50 mL) at ambienttemperature was added LiAlH₄ (9.4 mL, 9.4 mmol; 1M THF solution). After1.0 h the reaction was quenched with sat. NaK tartrate solution. Themixture was poured into a EtOAc/H₂ O mixture. The organic portion waswashed with brine, dried (MgSO₄) and concentrated to give 3-4 as ayellow viscous oil.

¹ H NMR (300 MHz, CDCl₃) δ 7.44 (s, 1H), 7.40-7.10 (m, 5H), 6.68 (s,1H), 5.03 (s, 2H), 3.87 (t, J=6 Hz, 2H), 2.77 (t, J=6 Hz, 2H).

Methyl 4- 2-(1-Benzylimidazol-4-yl)ethyloxy!benzoate (3-5)

A solution of 1-2 (152 mg, 1.0 mmol), PPh₃ (341 mg, 1.3 mmol), and THF(20 mL) was treated dropwise with DIAD (256 μL, 1.3 mmol) and 3-4 (202mg, 1.0 mmol) in THF (10 mL) over a 30 min period and then heated at 70°overnight. After 72 h, the reaction mixture was concentrated and thensubjected to flash chromatography (silica, 40% (CHCl₃ /NH₃)/EtOAc) togive 3-5 as a colorless oil. Rf 0.16 (silica, 40% (CHCl₃ /NH₃)/EtOAc).

¹ H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=9 Hz, 2H), 7.46 (s, 1H), 7.40-7.10(m, 5H), 6.89 (d, J=9 Hz, 2H), 6.74 (s, 1H), 5.04 (s, 2H), 4.28 (t, J=6Hz, 2H), 3.85 (s, 3H), 3.06 (t, J=6 Hz, 2H).

4- 2-(1-Benzylimidazol-4-yl)ethyloxy!benzoic acid. (3-6)

A mixture of 3-5 (170 mg, 0.51 mmol), 1N NaOH (5 mL), and CH₃ OH (10 mL)was stirred at ambient temperature for 20 h. The reaction mixture wascooled to 0° C., neutralized with 1N HCl (5 mL), and then concentrated.The solid was extracted with CHCl₃ and the combined extractsconcentrated to give 3-6 as a gelatinous solid.

₁ H NMR (300 MHz, CD₃ OD) δ 7.90 (d, J=9 Hz, 2H), 7.67 (s, 1H),7.40-7.20 (m, 5H), 6.95 (s, 1H), 6.88 (d, J=9 Hz, 2H), 5.16 (s, 2H),4.22 (t, J=6 Hz, 2H), 2.99 (t, J=6 Hz, 2H).

4-2-(1-Benzyl-imidazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alaninetert-butyl ester (3-7)

A stirred mixture of 3-6 (147 mg, 0.46 mmol), HOBT (94 mg, 0.61 mmol),2-1 (154 mg, 0.46 mmol), NMM (100 μL, 0.91 mmol), and DMF (1.2 mL) at 0°C. was treated with EDC (118 mg, 0.61 mmol) followed by removal of thecooling bath. The reaction pH was adjusted to 8 by addition of more NMM.After 20 h the reaction mixture was concentrated and the residuepurified by to a flash chromatography column (silica, 9/0.5/0.5 CH₂ Cl₂/CH₃ OH/AcOH) to give 3-7 as a yellow solid after azeotropic removal ofresidual AcOH with toluene. Rf 0.48 (silica, 9/0.5/0.5 CH₂ Cl₂ /CH₃OH/AcOH).

₁ H NMR (300 MHz, CDCl3) δ 7.87 (d, J=9 Hz, 2H), 7.80-7.10 (m, 11H),6.92 (d, J=9 Hz, 2H), 6.75 (s, 1H), 6.58 (m, 1H), 5.67 (m, 1H), 5.06 (s,2H), 4.29 (t, J=6 Hz, 2H), 3.90 (m, 2H), 3.56 (m, 1H), 3.06 (t, J=6 Hz,2H), 1.29 (s, 9H).

4-2-(1-Benzylimidazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alanine(3-8)

A solution of 3-7 (252 mg, 0.42 mmol), TFA (3 mL) and CH₂ Cl₂ (10 mL)was stirred at ambient temperature for 3 h, followed by concentration.Flash chromatography (silica, 9:0.5:0.5 ethanol/NH₄ OH/H₂ O (2x)) gave3-8 as a viscous gum. Rf 0.08 (silica, 9:0.5:0.5 ethanol/NH₄ OH/H₂ O).

¹ H NMR (300 MHz, CD₃ OD) δ 7.99 (s, 1H), 7.84 (d, 2H), 7.72 (d, 2H),7.40-7.20 (m, 8H), 7.06 (s, 1H), 6.92 (d, J=9 Hz, 2H), 5.22 (s, 2H),4.24 (t, J=6 Hz, 2H), 3.86 (m, 1H), 3.68 (dd, 1H), 3.53 (dd, 1H), 3.03(t, J=6 Hz, 2H).

4- 2-(Imidazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-βalanine(3-9)

A mixture of 3-8 (94 mg, 0.17 mmol), 10% Pd/C (94 mg), and 4.4% formicacid/CH₃ OH was stirred at ambient temperature under a hydrogenatmosphere (1 atm) for 72 h. The reaction mixture was filtered through acelite pad and the tiltrate concentrated. Flash chromatography (silica,5/3/0.5 CH₂ Cl₂ /CH₃ OH/32% AcOH; then 10/1/1 ethanol/NH₄ OH/H₂ O) gave3-9 as a colorless solid. Rf 0.33 (silica, 5/3/0.5 CH₂ Cl₂ /CH3OH/32%AcOH).

¹ H NMR (400 MHz, CD₃ OD) δ 7.85 (m, 3H), 7.77 (d, J=9 Hz, 2H), 7.50 (m,3H), 7.03 (s, 1H), 6.97 (d, J=9 Hz, 2H), 4.28 (t, J=6 Hz, 2H), 3.77 (m,1H), 3.67 (dd, 1H), 3.54 (dd, 1H), 3.11 (t, J=6 Hz, 2H). ##STR52## EthylIndol-2-ylacetate (4-1)

2-Methylindole (1.7 g, 13 mmol) in 130 mL Et₂ O was treated with nBuLi(1.6 M in hexane, 24.4 mL, 39 mmol) and KO^(t) Bu (1.0M in THF, 26 mL,26 mmol) at RT for 40 min, then diethylcarbonate (3.15 mL, 26 mmol) wasadded. After 1 h the reaction was quenched with water, adjusted to pH 7with 6N HCI, extracted with EtOAc, then the organic layer was washedwith water and brine, dried (MgSO₄), and concentrated. Flashchromatography (silica 10% then 20% EtOAc/hexane) provided 4-1 as abrown oil.

Rf 0.33 (silica, 20% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 8.67 (br s, 1H), 7.55 (dd, J═8,1 Hz, 1H),7.35 (dd, J=8, 1 Hz, 1H), 7.20-7.05 (m, 2H), 6.35 (m, 1H), 4.21 (q, J=7Hz, 2H), 3.83 (s, 2H), 1.30 (t, J=7 Hz, 3H).

2-(Indol-2-yl)ethanol (4-2)

Ester 4-1 (0.54 g, 2.6 mmol) was dissolved in 13 mL CH₂ Cl₂ at -78°, andDIBAL (1M in CH₂ Cl₂, 5.8 ml, 5.8 mmol) was added dropwise. The mixturewas stirred at -78° for 15 min then warmed to RT for 30 min and quenchedin sat. aqueous Na/K tartrate. This solution was extracted with EtOAc.The organic layer was washed with brine, dried (Na₂ SO₄), andconcentrated. Flash chromatography (silica 50% EtOAc/hexane) provided4-2 as a brown oil.

Rf 0.38 (silica, 50% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 8.43 (br s, 1H), 7.54 (dd, J=8, 1 Hz, 1H),7.32 (dd, J=8, 1 Hz, 1H), 7.20-7.05 (m, 2H), 6.29 (m, 1H), 3.9 (q, J=5Hz, 2H), 3.02 (t, J=5 Hz, 2H).

Methyl 4 2-(Indol-2-yl)ethyloxy!benzoate (4-3)

Alcohol 4-2 (136 mg, 0.84 mmol), phenol 1-2 (128 mg, 0.84 mmol) and Ph₃P (277 mg, 1.06 mmol) were combined in 8 mL THF, and a solution of DIAD(0.22 mL, 1.1 mmol) in 5 mL THF was added dropwise during 1.5 h. After2.5 h the mixture was diluted with EtOAc, washed with water/brine, 1NNaOH, and brine, dried (MgSO₄), and concentrated. Flash chromatography(silica 15% EtOAc/hexane) provided 4-3 as an oil.

Rf 0.14 (silica, 15% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ8.25 (br s, 1H), 8.01 (dd, J=9 Hz, 2H), 7.55(dd, J=8, 1 Hz, 1H), 7.34 (dd, J=8, 1 Hz, 1H), 7.20-7.05 (m, 2H), 6.97(d, J=9 Hz, 2H), 6.34 (m, 1H), 4.34 (t, J=6 Hz, 2H), 3.89 (s, 3H), 3.28(t, J=6 Hz, 2H).

4- 2-(Indol-2-yl)ethyloxy!benzoic acid (4-4).

Ester 4-3 (150 mg, 0.51 mmol) and 1N NaOH (1.3 mL, 1.3 mmol) werecombined in 10 mL MeOH. After 16 h additional 1N NaOH (5 mL, 5 mmol) wasadded, and 7 h later, 5 mL more 1N NaOH. After a total of 2 d themixture was heated at 50° for 1 h, then concentrated, redissolved in H₂O, washed with EtOAc, and the pH of the aqueous layer was adjusted to 1with 20% KHSO₄. This was extracted with EtOAc, and this organic layerwas washed with brine, dried (MgSO₄) and concentrated, providing 4-4 asa gray solid.

Rf 0.48 (silica, EtOAc).

¹ H NMR (300 MHz, CD₃ OD) δ 7.96 (d, J=9 Hz, 2H), 7.42 (ds J=8 Hz, 1H),7.29 (dd, J=8, 1 Hz, 1H), 7.02 (d, J=9 Hz, 2H), 7.03-6.93 (m, 2H), 6.27(s, 1H), 4.37 (t, J=7 Hz, 2H), 3.25 (t, J=7 Hz, 2H).

4- 2-(Indol-2-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninemethyl ester (4-5)

Acid 4-4 (100 mg, 0.36 mmol), amine 2-2 (105 mg, 0.36 mmol), EDC (88mg., 0.46 mmol), HOBT (62 mg, 0.46 mmol) and NMM (137 μL, 1.2 mmol) werecombined in 2 mL DMF. After 16 h the mixture was diluted with EtOAc,washed with water, sat. NaHCO₃, 5% KHSO₄, and brine, dried (MgSO₄) andconcentrated. Flash chromatography (silica, 65% EtOAc/hexane) provided4-5 as an oil.

Rf 0.32 (silica, 65% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ8.41 (br s, 1H), 7.83 (d, J=7 Hz, 2H), 7.74(d, J=9 Hz, 2H), 7.60-7.43 (m, 4H), 7.34 (dd, J=8, 1 Hz, 1H), 7.20-7.02(m, 2H), 6.93 (d, J=9 Hz, 2H), 6.72 (br t, 1H) 6.34 (m, 1H), 5.87 (d,J=8 Hz, 1H), 4.28 (t, J=6 Hz, 2H), 4.05 (m, 1H), 3.86 (m 1H), 3.67 (m,1H), 3.60 (s, 3H), 3.26 (t, J=6 Hz, 2H).

ps 4-2-(Indol-2-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine(4-6)

Ester 4-5 (147 mg, 0.28 mmol), and 1 N LiOH (0.70 mL, 0.70 mmol), werecombined in 3 mL THF. After 16 h the mixture was concentrated andpurified by flash chromatography (silica, 33:20:1:1 EtOAc/EtOH/NH₄ OH/H₂O) providing 4-6 as a white solid.

Rf 0.33 (silica, 33:20:1:1 EtOAc/EtOH/NH₄ OH/H₂ O ).

¹ H NMR (300 MHz, DMSO) δ 8.46 (br s, 1H), 7.77 (d, J=7 Hz, 2H), 7.71(d, J=9 Hz, 2H), 7.60-7.46 (m, 3H), 7.41 (d, J=8 Hz, 1H), 7.29 (d, J=8Hz, 1H), 7.02 (d, J=9 Hz, 2H), 7.02-6.86 (m, 4H), 6.26 (br s,1H), 4.35(t, J=7 Hz, 2H), 3.60-3.20 (m), 3.19 (t, J=7 Hz, 2H). ##STR53##4-Hydroxybenzoyl-2(S)-phenylsulfonylamino-β-alanine tert-butyl ester(5-2)

To a stirred solution of 5-1 (0.41 g, 2.9 mmol; Aldrich), 2-1 (1.0 g,2.9 mmol), HOBT (0.52 g, 3.9 mmol) NMM (0.65 mL, 5.9 mmol), and DMF (15mL) at 0° C. was added EDC (0.74 g, 3.9 mmol) followed by removal of thecooling bath. After 20 h, the reaction mixture was diluted with EtOAcand then washed with H₂ O (2x), sat. NaHCO₃, 5% KHSO₄ and brine, dried(MgSO₄), filtered and concentrated. Flash chromatography (silica, 60% to80% EtOAc/hexanes), then redissolving in EtOAc, washing with water (2x)and brine, drying, filtering and concentrating gave 5-2 as a white foam.

Rf 0.38 (silica, 60% EtOAc/hexanes).

¹ H NMR (300 MHz, CDCl₃) δ 7.86 (m, 2H), 7.72 (d, J=9 Hz, 2H), 7.53 (m,3H), 6.87 (d, J=9 Hz, 2H), 6.62 (m, 1H), 5.63 (d, J=7 Hz, 1H), 5.42 (m,1H), 3.90 (m, 2H), 3.55 (m, 1H), 1.29 (s, 9H).

2-(2-Aminothiazol-4-yl) ethanol (5-4)

To a stirring suspension of 5-3 (2.0 g, 10.7 mmol; Fluka) in ether (54mL) at ambient temperature was added LiAlH₄ (16.1 mL, 16.1 mmol; 1M/THF)dropwise. After complete addition, the reaction mixture was stirred for30 min and then quenched by sequential addition of H₂ O (0.61 mL), 15%NaOH (0.61 mL), and H₂ O (1.83 mL). The reaction mixture was filteredthrough a celite pad and the filtrate concentrated to give 5-4 as abrown oil.

Rf 0.26 (silica, 5:1:1 CH₂ Cl₂ /CH₃ OH/AcOH).

¹ H NMR (400 MHz, DMSO) δ 6.81 (s, 1H), 3.76 (t, J=6 Hz, 2H), 2.88 (t,J=6 Hz, 2H).

4-2-(2-Aminothiazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninetert-butyl ester (5-5)

To a stirred solution of 5-2 (0.14 g, 0.32 mmol) and PPh₃ (0.11g, 0.41mmol) in THF (2 mL) at ambient temperature was added a solution of 5-4(56 μg, 0.39 mmol) DEAD (67 μL, 0.42 mmol) in THF (2 mL) dropwise over a15 min period. After 72 h, the reaction mixture was diluted with EtOAcand then washed with H₂ O, sat. NaHCO₃, 10% KHSO₄ and brine, dried(MgSO₄) and concentrated. After two flash columns: silica, 85%EtOAc/hexanes; silica, 5% to 30% isopropanol/CHCl₃), 5-5 was obtained asa yellow oil. Rf 0.19 (silica, 85% EtOAc/hexanes).

¹ H NMR (400 MHz, CDCl₃) δ 7.86 (m, 2H), 7.73 (d, J=9 Hz, 2H), 7.52 (m,3H), 6.92 (d, J=9 Hz, 2H), 6.67 (m, 1H), 6.22 (s, 1H), 5.81 (m, 1H), 5.5(m, 2H), 4.24 (t, J=6 Hz, 2H), 3.90 (m, 2H), 3.56 (m, 1H), 3.02 (t, J=6Hz, 2H), 1.28 (s, 9H).

4- 2-(2-Aminothiazol-4-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine (5-6)

A stirred solution of 5-5 (33 mg, 60 μmol), CH₂ Cl₂ (0.5 mL), andtriethylsilane (24 μL, 0.15 mmol) at ambient temperature was treatedwith TFA (0.5 mL). After 4 h, the solution was concentrated and theresidual TFA removed azeotropically with toluene. Flash chromatography(silica, 10:0.1:0.1 ethanol/NH₄ OH/H₂ O) gave 5-6 as a white solid.

¹ H NMR (400 MHz, D₂ O+DCl) δ 7.49 (m, 2H), 7.30 (d, J=9 Hz, 2H), 7.08(m, 3H), 6.73 (d, J=9 Hz, 2H), 4.11 (t, 2H), 3.97 (m, 1H), 3.50 (m, 1H),3.38 (m, 1H), 3.20 (m, 1H) 2.82 (m, 2H). ##STR54## 4-N-BOC-Aminobutanol(6-2)

To a stirred solution of 6-1 (Aldrich) (5.0 g, 56 mmol), NEt₃ (11.7 mL,84 mmol), and DMF (150 mL) at 0° C. was added BOC₂ O (14.7 g, 67 mmol)followed by removal of the cooling bath. After 1.0 h, the solution wasdiluted with EtOAc and then washed with 10% KHSO₄ and brine, dried(MgSO₄) and concentrated to give 6-2 as a colorless oil.

¹ H NMR (300 MHz, CDCl₃) δ 3.68 (m, 2H), 3.15 (m,2H), 1.60 (m, 4H), 1.47(s, 9H).

N-Cbz-L-Tyrosine methyl ester (6-4)

A suspension of Cs₂ CO₃ (0.65 g, 2.0 mmol), N-Cbz-L-tyrosine (1.3 g, 4.0mmol; Bachem) and DMF (40 mL) at ambient temperature was treated withmethyl iodide (0.5 mL, 4.0 mmol). After 2.0 h the reaction mixture wasdiluted with EtOAc and then washed with H₂ O and brine, dried (MgSO₄)and concentrated. Flash chromatography (silica, 25% EtOAc/hexanes) gave6-4 as a white solid.

Rf 0.53 (silica, 50% EtOAc/hexanes).

Methyl 2(S)-(N-Benzyloxycarbonylamino)-3-4-(4-N-Boc-aminobutyloxy)phenyl!propionate (6-5)

To a stirred solution of 6-4 (500 mg, 1.5 mmol), PPh₃ (0.5 g, 1.9 mmol)and THF (10 mL) was added a solution of 6-2 (430 mg, 2.3 mmol), DEAD(326 mg, 1.9 mmol), and THF (10 mL) dropwise over a 30 min period. After2.0 h the solution was diluted with EtOAc and then washed with H_(2O),1N NaOH, 10% KHSO₄ and brine, dried (MgSO₄) and concentrated. Flashchromatography (silica, 25% EtOAc/hexanes) gave 6-5 as a white solid. Rf0.50 (silica, 50% EtOAc/hexanes).

¹ H NMR (300 MHz, CD₃ OD) δ 7.22 (m, 5H), 7.02 (d, J=9 Hz, 2H), 6.72 (d,J=9H, 2H), 4.97 (m, 2H), 4.34 (m, 1H), 3.89 (m, 2H), 3.63 (s, 3H), 3.02(m, 2H), 3.01 (m, 1H), 2.81 (m, 1H), 1.73 (m, 2H), 1.62 (m, 2H), 1.47(s, 9H).

Methyl 2(S)-amino-3- 4-(4-N-Boc-aminobutyloxy)phenyl!propionate (6-6)

A mixture of 6-5 (500 mg, 0.99 mmol), 10% Pd/C (250 mg), and EtOAc (5mL) was stirred under a hydrogen atmosphere (1 atm) at ambienttemperature for 1.0 h. The reaction mixture was then filtered through acelite pad and the filtrate concentrated to give 6-6 as a yellow solid.Rf 0.36 (silica, 10:1:1 CH₂ Cl₂ /CH₃ OH/AcOH).

¹ H NMR (300 MHz, CD₃ OD) δ 7.02 (d, J=9 Hz, 2H), 6.80 (d, J=9 Hz, 2H),3.90 (m, 2H), 3.63 (s, 3H), 3.03 (m, 2H), 2.85 (m, 2H), 1.73 (m, 2H),1.62 (m, 2H), 1.47 (s, 9H).

Methyl 2(S)-phenylsulfonylamino-3-4-(4-N-Boc-aminobutyloxy)-phenyl!propionate (6-7)

To a stirred solution of 6-6 (350 mg, 0.95 mmol), CH₂ Cl₂ (5 mL), andpyridine (229 μL, 3.0 mmol) at 0° C. was added phenyl-sulfonyl chloride(145 μL, 1.2 mmol), followed by removal of the cooling bath. After 20 hthe reaction mixture was diluted with EtOAc and then washed with H₂ Osat. NaHCO₃, 10% KHSO₄ and brine, dried (MgSO₄) and concentrated. Flashchromatography (silica, 30% EtOAc/hexanes) gave 6-7 as a colorless oil.Rf 0.31 (silica, 30% EtOAc/hexanes).

¹ H NMR (300 MHz, CD₃ OD) δ 7.25-7.00 (m, 5H), 6.52 (d, J=9 Hz, 2H),6.30 (d, J=9 Hz, 2H), 3.58 (m, 1H), 3.50 (t, 2H), 2.97 (s, 3H), 2.67 (t,2H), 2.45 (dd, 1H), 2.32 (dd, 1H), 1.32 (m, 2H), 1.21 (m, 2H), 1.01 (s,9H).

2(S)-Phenylsulfonylamino-3- 4-(4-N-Boc-aminobutyloxy)phenyl!-propionicacid (6-8)

A solution of 6-7 (350 mg, 0.69 mmol), 1N NaOH (1.5 mL), and ethanol(3.5 mL) was stirred at ambient temperature for 1.0 h. The solution wasthen acidified with 10% KHSO₄ and extracted with EtOAc. The EtOAcportion was washed with brine, dried (MgSO₄) and concentrated to give6-8 as a white solid.

Rf 0.71 (silica, 10:1:1 CH₂ Cl₂ /CH₃ OH/AcOH).

¹ H NMR (300 MHz, CD₃ OD) δ7.60-7.30 (m, 5H), 6.92 (d, J=9 Hz, 2H), 6.63(d, J=9 Hz, 2H), 3.87 (m, 3H), 3.02 (t, 2H), 2.88 (dd, 1H), 2.68 (dd,1H), 1.70 (m, 2H), 1.58 (m, 2H), 1.45 (s, 9H).

2(S)-Phenylsulfonylamino-3- 4-(4-guanidobutyloxy)phenyl!propionic acid(6-9)

A solution of 6-8 (300 mg, 0.60 mmol), TFA (3 mL), and CH₂ Cl₂ (3 mL)was stirred at ambient temperature for 1.0 h. The solution wasconcentrated followed by azeotropic removal of the residual TFA withtoluene. The residue was dissolved in 1:1 DMF/H₂ O (3.0 mL) and thentreated with N(i-Pr)₂ Et (316 μL, 1.8 mmol) and DPFN (1.33 mg, 0.91mmol). After heating at 40° C. for 2.0 h the reaction mixture wasconcentrated. Flash chromatography (silica, 10/0.1/0.1 to 10/1/1ethanol/NH₄ OH/H₂ O) gave 6-9 as a white solid.

Rf 0.33 (silica, 10:1:1 ethanol/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, CD₃ OD) δ7.75-7.45 (m, 5H), 7.06 (d, J=9 Hz, 2H), 6.78(d, J=9 Hz, 2H), 4.02 (m, 3H), 3.30 (m, 2H), 3.00 (dd, 1H), 2.79 (dd,1H), 1.77 (m, 4H). ##STR55## 2-S-(N-Benzyloxycarbonylamino)-3-4-(5-guanidopentyloxy)-phenyl!propionic acid (7-2)

A stirred solution of 7-1 (225 mg, 0.56 mmol; for preparation seeDuggan, et al, European Publication 478362), diisopropylethylamine (0.6mL, 3.4 mmol), DMF (4 mL), and H₂ O (1 mL) was treated with3,5-dimethyl-1-pyrazolylformaminidium nitrate (DPFN) (0.68 g, 3.4 mmol)then heated at 60° C. for 20 h.

Concentration followed by flash chromatography (silica, ethanol/NH₄OH/H_(2O) 10:0.3:0.3) gave 7-2 as a white solid.

Rf 0.59 (silica, 10:1:1 ethanol/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, CD₃ OD) δ 7.30 (m, 5H), 7.07 (d, 2H), 6.73 (d, 2H),5.07 (d, 1H), 4.98 (d, 1H), 4.21 (m, 1H), 3.96 (t, 2H), 3.16 (t, 2H),3.08 (dd, 1H), 2.89 (dd, 1H), 1.80-1.50 (m, 6H). ##STR56##3-(N-BOC-Amino)propanol (8-2)

To a stirred solution of 3-aminopropanol 8-1 (Aldrich) (15 g, 0.2 mol),NEt₃ (42 mL, 0.3 mol) and DMF (400 mL) at 0° C. was added BOC₂ O (52 g,0.24 mol). After stirring at 0° C. for 6 h the reaction mixture wasdiluted with ether and then washed with H₂ O (2x), sat. NaHCO₃, 5% KHSO₄and brine, dried (MgSO₄) and concentrated to give 8-2 as a colorlessoil.

TLC Rf 0.42 (silica, 20% EtOAc/hexanes);

¹ H NMR (300 MHz, CDCl₃) δ 3.68 (t, J=7 Hz, 2H), 3.30 (t, J=7 Hz, 2H),1.69 (m, 2H), 1.45 (s, 9H).

Methyl 4-(3-N-BOC-Aminopropyloxy)benzoate (8-3)

Following the procedure for coupling 1-1 to 1-2, 8-2 (13.8 g, 79 mmol)was coupled to 1-2 (8.0 g, 53 mmol) to give 8-3 as a yellow oil afterflash chromatography (silica, 5% EtOAc/hexanes).

TLC Rf=0.38 (silica, 20% EtOAc/hexanes);

¹ H NMR (300 MHz, CDCl₃) δ 8.00 (d, J=9 Hz, 2H), 6.92 (d, J=9 Hz, 2H),4.70 (m, 1H), 4.08 (m, 2H), 3.88 (s, 3H), 3.33 (m, 2H), 2.00 (m, 2H),1.46 (s, 9H).

4-(3-N-BOC-Aminopropyloxy)benzoic acid (8-4)

A solution of 8-3 (16 g, 52 mmol), 1N NaOH (100 mL), and ethanol (150mL) was stirred at ambient temperature for 20 h. The reaction mixturewas acidified with 10% KHSO₄ and then extracted with EtOAc. The EtOAcportion was washed with brine, dried (MgSO₄) and concentrated.Trituration of the residue with ether gave 8-4 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.87 (d, J=9 Hz, 2H), 6.88 (d, J=9 Hz, 2H),3.98 (t, J=6 Hz, 2H), 3.15 (t, J=6 Hz, 2H), 1.86 (m, 2H), 1.33 (s, 9H).

4- 3-(N-BOC-Amino)propyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninetert-butyl ester (8-5)

Following the procedure for coupling 1-4 to 2-1, 8-4 (300 mg, 1.0 mmol)was coupled to 2-1 (372 mg, 1.2 mmol) to furnish 8-5 as a colorless oilafter flash chromatography (silica, 50% EtOAc/ hexanes).

TLC Rf 0.33 (silica, 50% EtOAc/hexanes);

¹ H NMR (300 MHz, 10% CD₃ OD/CDCl₃) δ 7.8 (m, 2H), 7.76 (d, J=9 Hz, 2H),7.51 (m, 3H), 6.92 (d, J=9 Hz, 2H), 4.10 (m, 2H), 4.00-3.60 (m, 3H),3.32 (m, 2H), 2.00 (m, 2H), 1.45 (s, 9H), 1.28 (s, 9H).

4-(3-Guanidopropyloxy)benzoyl-2(S)-phenylsulfonylamino-δ-alanine (8-6)

Following the procedure for converting 2-3 to 2-4, 8-5 (300 mg, 0.55mmol) furnished 8-6 as a white solid after flash chromatography (silica,10:1:1 ethanol/H₂ O/NH₄ OH).

TLC Rf 0.28 (silica, 10:1:1 ethanol/H_(2O/) NH₄ OH);

¹ H NMR (400 MHz, D₂ O) δ 7.65 (m, 2H), 7.43 (d, J=9 Hz, 2H), 7.24 (m,3), 6.90 (d, J=9 Hz, 2H), 4.13 (m, 1H), 4.10 (m, 2H), 3.68 (m, 1H), 3.52(m, 1H), 3.40-3.25 (m, 3H), 2.00 (m, 2H). ##STR57##4-(3-Aminopropyloxy)benzoyl-2(S)-phenylsulfonylamino-β-alaninetrifluoroacetate (9-1)

8-5 (497 mg, 1.04 mmol) in 5 mL CH₂ Cl₂ was treated with 5 mL TFA at 0°for 30 min then RT for 10 min. Concentration provided 9-1 as a yellowoil.

Rf 0.52 (silica, 10:1:1 ethanol/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, CD₃ OD) δ 7.9-7.6 (m, 4H) 7.55-7.45 (m, 3H), 7.02 (d,2H), 4.18 (t, 2H), 3.70 (m, 1H), 3.48 (m, 1H), 3.16 (t, 2H), 3.05, (m,1H), 2.16 (qn, 2H).

4- 3-(Formamido)propyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine(9-2)

The TFA salt 9-1 (80 mg, 0.19 mmol) was dissolved in water at 0° and thepH of the solution was adjusted to 9 by addition of 1N NaOH. Isopropylformimidate hydrochloride (130 mg, 0.95 mmol) was added in two portions10 min apart maintaining pH 9 with additional 1N NaOH. After 60 rain at0° the reaction was warmed to RT for 90 min, then lyophylized.Preparative HPLC (C-18, 0.1% TFA H₂ O/CH₃ CN) provided 9-2 as a whitesolid.

¹ H NMR (400 MHz, D₂ O) 7.81 (s, 1H), 7.77 (d, J=7 Hz, 2H), 7.60 (d, J=9Hz, 2H), 7.46-7.35 (m, 3H), 7.05 (d, J=9 Hz, 2H), 4.23 (t, J=6 Hz, 2H),3.91 (dd, J=10, 4 Hz, 1H), 3.68 (dd, J=14, 4 Hz, 1H), 3.56 (t, J=6 Hz,2H), 3.40 (dd, J=14, 10, 1H), 2.19 (qn, J=6 Hz, 2H). ##STR58## Methyl3-methoxy-4-(3-N-BOC-aminopropyloxy)benzoate (10-2)

Following the procedure for coupling 1-1 to 1-2, 8-2 (2.8 g, 16.1 mmol)was coupled to 10-1 (Aldrich) (1.9 g, 10.7 mmol) to give 10-2 as acolorless oil after flash chromatography (silica, 20% EtOAc/hexanes).

TLC Rf 0.18 (silica, 20% EtOAc/hexanes);

¹ H NMR (300 MHz, CDCl₃) δ7.70 (dd, J=9 and 2 Hz, 1H), 7.57 (d, J=2 Hz,1H), 6.89 (d, J=9 Hz, 1H), 5.52 (m, 1H), 4.17 (m, 2H), 3.96 (s, 3H),3.92 (s, 3H), 3.40 (m, 2H), 2.08 (m, 2H), 1.48 (s, 9H).

3-Methoxy-4-(3-N-BOC-aminopropyloxy)benzoic acid (10-3)

A solution of 10-2 (3.5 g, 10.2 mmol), 1N NaOH (20 mL) and ethanol (30mL) was heated at 60° C. for 2.0 h. The cooled reaction mixture wasacidified with 10% KHSO₄ and extracted with EtOAc.

The organic portion was washed with brine, dried (MgSO₄) andconcentrated. The residue was triturated with Et₂ O and filtered to give10-3 as a white solid.

¹ H NMR (400 MHz, CD₃ OD) δ7.68 (dd, J=9, 2 Hz, 1H), 7.60 (d, J=2 Hz,1H), 7.02 (d, J=9 Hz, 1H), 4.15 (m, 2H), 3.92 (s, 3H), 3.30 (m, 2H),2.03 (m, 2H), 1.47 (s, 9H).

3-Methoxy-4- 3-(N-BOC-amino)propyloxy!benzoyl-2(S)-phenyl-sulfonylamino-β-alaninetert-butylester (10-4)

Following the procedure for coupling 1-4 to 2-1, 10-3 (230 mg, 0.71mmol) was coupled to 2-1 (215 mg, 0.71 mmol) to give 10-4 as a whitesolid after flash chromatography (silica, 50% EtOAc/hexanes).

TLC Rf 0.31 (silica, 50% EtOAc/hexanes);

¹ H NMR (300 MHz, CD₃ OD) δ 7.80-7.30 (m, 7H), 6.93 (d, J=9 Hz, 1H),6.61 (m, 1H), 4.05 (m, 3H), 3.82 (s, 3H), 3.61 (m, 1H), 3.43 (m, 1H),3.22 (m, 2H), 1.92 (m, 2H), 1.47 (s, 9H), 1.18 (s, 9H).

3-Methoxy-4-3-guanidinopropyloxy!benzoyl-2(S)-phenylsulfonyl-amino-β-alanine (10-5)

A solution of 10-4 (350 mg, 0.61 mmol), TFA (3 mL) and CH₂ Cl₂ (3 mL)was stirred at ambient temperature for 3.0 h. The reaction mixture wasconcentrated and the residual TFA removed azeotropically with toluene.The residue was dissolved in DMF (1.5 mL) and H₂ O (1.5 mL) and treatedsequentially with DIPEA (317 μl, 1.8 mmol) andpyrazole-1-carboxamidine·HCl (PCA·HCl) (134 mg, 0.92 mmol). After 20 hat ambient temperature the reaction mixture was concentrated. Flashchromatography (silica, 10:1:1 ethanol/NH₄ OH/H₂ O) gave 10-5 as a whitesolid.

TLC Rf=0.18 (silica, 10:1:1 ethanol/NH₄ OH/H₂ O);

¹ H NMR (400 MHz, CD₃ OD) δ 7.90-7.40 (m, 7H), 7.08 (d, J=9 Hz, 1H),4.27 (m, 1H), 4.22 (m, 2H), 3.96 (s, 3H), 3.82-3.45 (m, 4H), 2.15 (m,2H). ##STR59## Methyl 3-(3-N-BOC-Aminopropyloxy)benzoate (11-2)

Following the procedure for coupling 1-1 to 1-2, 8-2 (2.8 g, 16.1 mmol)was coupled to 11-1 (Aldrich) (1.6 g, 10.7 mmol) to give 11-2 as acolorless oil after flash chromatography (silica, 15% EtOAc/hexanes).

TLC Rf 0.28 (silica, 15% EtOAc/hexanes);

¹ H NMR (400 MHz, CD₃ OD) δ 7.62 (m, 1H), 7.56 (m, 1H), 7.40 (m, 1H),7.19 (m, 1H), 4.09 (m, 2H), 3.93 (s, 3H), 3.27 (m, 2H), 1.99 (m, 2H),1.47 (s, 9H).

3-(3-N-BOC-Aminopropyloxy)benzoic acid (11-3)

A solution of 11-2 (3.3 g, 10.7 mmol), 1N NaOH (30 mL) and ethanol (50mL) was heated at 60° C. for 20 h. The cooled reaction mixture wasacidified with 10% KHSO₄ and then extracted with EtOAc.

The organic portion was washed with brine, dried (MgSO₄) andconcentrated to give 11-3 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.63 (m, 1H), 7.58 (m, 1H), 7.40 (m, 1H),7.18 (m, 1H), 4.08 (m, 2H), 3.27 (m, 2H), 2.00 (m, 2H), 1.47 (s, 9H).

3- 3-(N-BOC-Aminopropyloxy)!benzoyl-2(S)-phenylsulfonylamino-βalaninetert-butyl ester (11-4)

Following the procedure for coupling 1-4 to 2-1, 11-3 (2.86 mg, 1.0mmol) was coupled to 2-1 (296 mg, 1.0 mmol) to give 11-4 as a colorlessoil after flash chromatography (silica, 50% EtOAc/hexanes).

TLC Rf=0.27 (silica, 50% EtOAc/hexanes);

¹ H NMR (300 MHz, CD₃ OD) δ 7.67 (m, 2H), 7.32 (m, 3H), 7.13 (m, 3H),6.91 (m, 1H), 4.03 (m, 1H), 3.95 (m, 2H), 3.55 (m, 1H), 3.39 (m, 1H),3.12 (m, 2H), 1.88 (m, 2H), 1.32 (s, 9H), 1.16 (s, 9H).

3 - 3-(Guanidino)propyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine(11-5)

Following the procedure for convening 10-4 to 10-5, 11-4 (350 mg, 0.64mmol) was heated at 40° C. for 3.0 h to give 11-5 as a white solid afterflash chromatography (silica, 10:1:1 ethanol/NH₄ OH/H₂ O).

TLC Rf=0.28 (silica, 10:1:1 ethanol/NH₄ OH/H₂ O);

¹ H NMR (400 MHz, CD₃ OD) δ 7.77 (m, 2H), 7.60-7.25 (m, 6H), 7.18 (m,1H), 4.28 (m, 1H), 4.18 (m, 2H), 3.73 (m, 1H), 3.56 (m, 1H), 3.47 (m,2H), 2.13 (m, 2H). ##STR60##4-(2-Aminoethyloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine.multidot.HCl(12-1)

A suspension of 2-3 (105 mg, 0.19 mmol) in 6N HCl (5 mL) was treatedwith dioxane (5 mL) to effect a homogeneous solution. After stirring for20 h at ambient temperature, the solvents were evaporated and theresulting residue azeotroped with toluene to afford 12-1 as a colorlesssolid.

TLC Rf 0.48 (silica, 9:0.5:0.5 ethanol/H₂ O/NH₄ OH).

¹ H NMR (300 MHz, CD₃ OD) δ 7.82 (m, 2H), 7.78 (d, J=9H, 2H), 7.48 (m,3H), 7.07 (d, J=9 Hz, 2H), 4.30 (m, 2H), 4.19 (m, 1H), 3.73 (m, 1H),3.48 (m, 1H), 3.40 (m, 2H).

4-2-(N-Phenylguanidino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine(12-3)

A mixture of 12-1 (110 mg, 0.25 mmol), 12-2 (147 mg, 0.50 mmol), DIPEA(174 μL, 1.0 mmol) and DMF (5 mL) was stirred for 24 h at ambienttemperature. Concentration and flash chromatography (silica,9.5:0.25:0.25 ethanol/NH₄ OH/H₂ O) gave 12-3 as a colorless solid.

TLC Rf 0.50 (silica, 9.5:0.25:0.25 ethanol/NH₄ OH/H₂ O);

¹ H NMR (400 MHz, CD₃ OD) δ 7.77 (m, 2H), 7.72 (d, J=9 Hz, 2H),7.60-7.20 (m, 8H), 7.02 (d, J=9 Hz, 2H), 4.70 (m, 1H), 4.22 (m, 2H),3.73 (m, 2H), 3.67 (m, 1H), 3.56 (m, 1H). ##STR61##N,N-Dimethylthiomethyl amidine·HI (13-2)

The thiourea 13-1 (TransWorld) (5.0 g, 48 mmol) was suspended in ethanol(50 mL) at ambient temperature and treated with methyl iodide (4.5 mL,72 mmol). After 2.0 h the reaction mixture was concentrated and theresidue triturated with ether to give 13-2 as a pale yellow solid.mp=97-100° C.

¹ H NMR (300 MHz, CD₃ OD) δ 3.31 (s, 3H), 3.27 (s, 3H), 2.68 (s, 3H).

4-2-(N,N-Dimethylguanidino)ethyloxy!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alanine·TFAsalt (13-3)

A solution of 13-2 (246 mg, 1.0 mmol), 12-1 (222 mg, 0.5 mmol), DIPEA(261 μL, 1.5 mmol) and DMF (5 mL) was heated at 100° C. for 18 h. Thereaction mixture was then concentrated. Flash chromatography (silica,9:0.5:0.5 to 9:1:1 ethanol/H₂ O/NH₄ OH) gave 13-3 as a colorless solidafter lyophilization.

TLC Rf 0.22 (silica, 9:1:1 ethanol/NH₄ OH/H₂ O);

¹ H NMR (300 MHz, CD₃ OD) δ 7.88 (m, 2H), 7.80 (m, 2H), 7.52 (m, 3H),7.00 (d, J=9 Hz, 2H), 4.20 (m, 2H), 3.80-3.50 (m, 4H), 3.30 (bs, 6H),3.03 (s, 3H). ##STR62## Methyl 4-(nitrophen-3-yloxy)benzoate (14-2)

A mixture of 14-1 (Aldrich) (1.6 g, 10 mmol), 1-2 (1.5 g, 10 mmol), K₂CO₃ (1.4 g, 10 mmol) and DMF (20 mL) was refluxed for 7.0 h. Aftercooling most of the DMF was removed in vacuo. The dark residue wasdiluted with ether and then washed with H₂ O and brine, dried (MgSO₄)and concentrated. Flash chromatography (silica, 20% ether/hexanes) gave14-2 as a yellow solid.

TLC Rf 0.16 (silica, 20% ether/hexanes);

¹ H NMR (300 MHz, CDCl₃) δ 8.10 (d, J=9 Hz, 2H), 8.03 (m, 1H), 7.87 (m,1H), 7.55 (m, 1H), 7.40 (m, 1H), 7.06 (d, J=9 Hz, 2H), 3.93 (s, 3H).

4-(Nitrophen-3-yloxy)benzoic acid (14-3)

A solution of 14-2 (160 mg, 0.58 mmol), 1N NaOH (5.8 mL) and CH₃ OH (10mL) was stirred at ambient temperature for 24 h. The reaction mixturewas concentrated and the residue dissolved in H₂ O and washed withether. The aqueous portion was then acidified with NaHSO₄ and extractedwith EtOAc (2x). The combined EtOAc portions were dried (MgSO₄) and thenconcentrated to give 14-3 as a pale yellow solid.

¹ H NMR (300 MHz, CDCl₃) δ 8.18 (d, J=9 Hz, 2H), 8.07 (m, 1H), 7.91 (m,1H), 7.58 (m, 1H), 7.42 (m, 1H), 7.10 (d, J=9 Hz, 2H).

4-(Nitrophen-3 -yloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine methylester (14-4)

A solution of 14-3 (340 mg, 1.3 mmol), 2-2 (386 mg, 1.3 mmol), HOBT (271mg, 1.8 mmol), and DMF (6 mL) at -15° C. was treated with EDC (339 mg,1.8 mmol). The pH of the solution was adjusted to about 8.0 with NMMfollowed by removal of the cooling bath. After 20 h the reaction mixturewas concentrated and the residue dissolved in EtOAc. The EtOAc solutionwas washed with H₂ O, sat. NaHCO₃ and brine, dried (MgSO₄) andconcentrated. Flash chromatography (silica, 5% to 10% acetone/CH₂ Cl₂)gave 14-4 as a colorless foam.

TLC Rf 0.14 (silica, 5% acetone/CH₂ Cl₂);

¹ H NMR (300 MHz, CDCl₃) δ 8.01 (m, 1H), 7.85 (m, 5H), 7.53 (m, 4H),7.36 (m, 1H), 7.08 (d, J=9 Hz, 2H), 6.80 (m, 1H), 5.80 (m, 1H), 4.10 (m,1H), 3.93 (m, 1H), 3.69 (m, 1H), 3.67 (s, 3H).

4-(Nitrophen-3 -yloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine (14-5)

Following the procedure for convening 14-2 to 14-3, 14-4 (608 mg, 1.2mmol) was saponified at 60° C. to give 14-5 as a pale yellow solid.

¹ H NMR (300 MHz, CD₃ OD) δ 8.05 (m, 1H), 7.85 (m, 5H), 7.65 (m, 1H),7.48 (m, 4H), 7.12 (d, J=9 Hz, 2H), 4.21 (m, 1H), 3.75 (m, 1H), 3.52 (m,1H).

4-(Aminophen-3-yloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine (14-6)

A mixture of 14-5 (560 mg, 1.2 mmol), 5% Pd/C (110 mg), and ethanol (50mL) was stirred under a hydrogen atmosphere (1 atm) at ambienttemperature for 8 h. Some precipitate had formed so the mixture washeated to dissolve the solid and then filtered hot through a celite padto remove the catalyst. Concentration of the filtrate gave 14-6 as acolorless solid.

TLC Rf 0.85 (silica, 9:0.5:0.5 ethanol/NH₄ OH/H₂ O;

¹ H NMR (300 MHz, CD₃ OD) δ 7.83 (d, J=7 Hz, 2H), 7.72 (d, J=9 Hz, 2H),7.46 (m, 3H), 7.10 (m, 1H), 6.98 (d, J=9 Hz, 2H), 6.55 (m, 1H), 6.42 (m,1H), 6.35 (m, 1H), 4.17 (m, 1H), 3.72 (m, 1H), 3.50 (m, 1H).

4-(Guanidinophen-3-yloxy)benzoyl-2(S)-phenylsulfonylamino-β-alanine(14-7)

A solution of 14-6 (45 mg, 0.10 mmol), PCA·HCl (14 mg, 0.1 mmol) andDMF/H₂ O (1:1; 1 mL) was heated at 120° C. for 20 h. Concentration andflash chromatography (silica, 9:0.5:0.5 ethanol/NH₄ OH/H₂ O) gave 14-7as a colorless solid.

TLC Rf0.20 (silica, 9:0.5:0.5 ethanol/NH₄ OH/H₂ O);

¹ H NMR (300 MHz, CD₃ OD/40% NaOD/D₂ O) δ 7.80 (m, 4H), 7.31 (m, 4H),7.00 (d, J=9 Hz, 2H), 6.79 (m, 1H), 6.68 (m, 1H), 6.60 (m, 1H), 3.67 (m,2H), 3.35 (m, 1H). ##STR63## Methyl4-(trichloromethyliminooxymethyl)benzoate (15-1)

Methyl 4-hydroxmethylbenzoate (Aldrich), (1.22 g, 7.35 mmol),trichloroacetonitrile (0.81 mL, 8.1 mmol), and DBU (0.11 mL, 0.74 "mmol)were combined in CH₂ Cl₂ at 0°. After warming to RT for 3 h the reactionmixture was concentrated and purified by flash chromatography (silica,40% EtOAc/hex) providing 15-1.

Rf 0.77 (silica, 50% EtOAc/hexane);

¹ H NMR (300 MHz, CDCl₃) δ 8.42 (s, 1H), 8.06 (d, J=8 Hz, 2H), 7.50 (d,J=9 Hz, 2H), 5.40 (s, 2H), 3.92 (s, 3H).

Methyl 4- 2-(N-Cbz-amino)ethyloxymethyl!benzoate (15-2)

Imidate 15-1 (1.5 g, 4.8 mmol) and N-Cbz-aminoethanol (1.0 g, 5.1 mmol)were combined with Et₂ O (50 ml), then TfOH (100 μL, 1.1 mmol) was added(exothermic). The reaction mixture was stirred at RT for 24 h, thenheated at reflux for 16 h before diluting with EtOAc, washing withwater, 10% KHSO₄, 1N NaOH, and brine, drying (MgSO₄) and concentration.Flash chromatography (silica, 20% then 40% EtOAc/hexane) provided 15-2as a clear oil.

Rf 0.53 (silica, 50% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 8.0 (d, J=8 Hz, 2H), 7.50-7.30 (m, 7H), 5.18(br m, 1H), 5.10 (s, 2H), 4.56 (s, 2H), 3.92 (s, 3H), 3.58 (br m, 2H),3.45 (br m, 2H).

4- 2-(N-Cbz-amino)ethoxymethyl!benzoic acid (15-3)

Ester 15-2 (500 mg, 1.46 mmol) and 1N NaOH (3.6 mL, 3.6 mmol) werecombined in 14 mL MeOH. After 3 h the mixture was concentrated, dilutedwith EtOAc, and extracted with H₂ O. The aqueous layer was acidifiedwith 10% KHSO₄ and extracted with EtOAc, and this organic layer waswashed with brine, dried (MgSO₄), and concentrated, providing 15-3 as awhite solid.

Rf 0.62 (silica, 19:1:1 CH₂ Cl₂ /MeOH/HOAc).

¹ H NMR (300 MHz, CD₃ OD) δ 8.0 (d, J=8 Hz, 2H), 7.5-7.3 (m, 7H), 5.07(s, 2H), 4.59 (s, 2H), 3.56 (t, J=5 Hz, 2H), 3.34 (t, J=5 Hz, 2H).

4-2-(N-Cbz-Amino)ethyloxymethyl!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester (15-4)

Acid 15-3 (300 mg, 0.91 mmol), amine 2-1 (325 mg, 0.91 mmol), EDC (209mg, 1.09 mmol), HOBT (148 mg, 1.10 mmol), and NMM (300 μL, 2.7 mmol)were combined in 4.5 mL DMF. After 16 h the mixture was diluted withEtOAc, washed with water, 10% KHSO₄, sat NaHCO₃, and brine, dried(MgSO₄), and concentrated. Flash chromatography (silica, 70%EtOAc/hexane) provided 15-4 as an off-white solid.

Rf 0.77 (silica, EtOAc).

¹ H NMR (400 MHz, CDCl₃) δ 7.79 (d, J=7 Hz, 2H), 7.72 (d, J=8 Hz, 2H),7.40-7.20 (m, 10H), 7.0 (br s, 1H), 5.26 (br m, 1H), 5.09 (s, 2H), 4.49(s, 2H), 3.80-3.70 (m, 2H), 3.5-3.45 (m, 3H), 3.41 (m, 2H), 1.24 (s,9H).

4-(2-Aminoethyloxymethyl)benzoyl-2(S)-phenylsulfonylamino-β-alanine(15-5)

Cbz-ester 15-4 (200 mg, 0.33 mmol) was treated with 4 mL 30% HBr in HOAcfor 2 h then concentrated and purified by flash chromatography (silica,50:1:1 EtOH/NH₄ OH/H₂ O) providing 15-5 as a white solid.

Rf 0.42 (silica, 20:1:1 EtOH/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, D₂ O) δ 7.66 (d, J=9 Hz, 2H) 7.52 (d, J=8 Hz, 2H),7.38 (d, J=8 Hz, 2H), 7.33-7.25 (m, 3H), 7.58 (s, 2H), 3.80 (dd, J=10, 4Hz, 1H), 3.66 (br t, J=5 Hz, 2H), 3.58 (dd, J=14, 4 Hz, 1H), 3.31 (dd,J=14, 10 Hz, 1H), 3.07 (br m, 2H).

4-2-(Guanidino)ethyloxymethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine(15-6)

Amine 15-5 (40 mg, 0.095 mmol), PCA·HCl (15 mg, 0.10 mmol), and DIPEA(35 mL, 0.20 mmol) were combined in 1 mL DMF and heated at 50° for 16 h.Concentration, and flash chromatography (silica, 20:1:1 EtOH/NH₄ OH/H₂O) provided 15-6 as a white solid.

Rf 0.19 (silica, 20:1:1 EtOH/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, D₂ O) δ 7.61 (d, J=8 Hz, 2H), 7.46 (d, J=7 Hz, 2H),7.31 (d, J=8 Hz, 2H), 7.28-7.18 (m, 3H), 4.51 (s, 2H), 3.75 (m, 1H),3.56 (m, 2H), 3.54-3.44 (m, 2H), 3.25 (m, 2H). ##STR64##2-(N-BOC-Amino)ethylamine (16-2)

Ethylenediamine (16-1) (Aldrich) (18.04 g, 0.50 mol) in CHCl₃ (200 ml)was treated with a solution of BOC₂ O (13.1 g, 0.06 moles) in CHCl₃ (100ml) at room temperature over 1 h. This was stirred for 16 h, filtered,and concentrated to give 16-2 as a clear oil.

Methyl 3- 2-(N-BOC-amino)ethylaminocarbonyl!benzoate (16-4)

A solution of methyl 3-carboxybenzoate (16-3) (Aldrich) (0.9 g, 5 mmol),16-2 (0.8 g, 5 mmol), and HOBT (0.74 g, 5.5 mmol) in DMF (20 ml) wastreated with Et₃ N (1.0 g, 10 mmol) followed by EDC (1.15 g, 6.0 mmol).After stirring for 16 h the solvent was removed, the residue was takenup in H₂ O (100 mL), and extracted with 3×75 ml portions of EtOAc. Theorganic extract was washed consecutively with 10% KHSO₄, brine, satd.NaHCO₃, brine, and dried (Na₂ SO₄). Solvent removal gave a residue thatwas purified by flash chromatography (silica, 95% hexanes/EtOAc) to givecrude 16-4. This was further purified by chromatography (silica,70%/acetone/hexanes) to give pure 16-4.

Rf 0.3 (silica, 70% hexanes/acetone).

¹ H NMR (300 MHz, CDCl₃) δ 8.46 (s, 1H), 8.13-8.20 (dd, 1H), 8.3-8.10(dd, 1H), 7.48-7.57 (t, 1H), 7.30-7.45 (m, 1H), 4.95-5.08 (m, 1H), 3.95(s, 3H), 3.52-3.62 (m, 2H), 3.38-3.48 (m, 2H), 1.42 (s, 9H).

3-2-(N-BOC-Amino)ethylaminocarbonyl!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alaninemethyl ester (16-6)

16-4 (0.98 g, 3.03 mmoles) was dissolved in THF(1)/MeOH(1)/H₂ O(1) (30ml) and treated with LiOH (0.38 g, 9.1 mmoles).

After 10 h, the solvent was removed, the residue acidified to pH 2-3with 10% KHSO₄ solution, and extracted with EtOAc. The organic extractwas dried (Na₂ SO₄), concentrated, and the residue was purified by flashchromatography (silica, 95% hexanes/EtOAc) to give the desired acid16-5.

This acid (0.46 g, 1.5 mmoles) was dissolved in DMF (20 ml) and treatedwith 2-2 (0.44 g, 1.5 mmoles), HOBT (0.22 g, 1.65 mmoles), NMM (0.45 g,4.5 moles) followed by EDC (0.34 g, 1.8 mmoles). After stirring at roomtemperature for 16 h, the solvent was removed and the residue was takenup in H₂ O (75 ml), and extracted with EtOAc. The organic extract waswashed with 10% KHSO₄, brine, dried (Na₂ SO₄) and concentrated to give16-6 as a white solid.

¹ H NMR (300 MHz, CDCl₃) δ 8.17 (s, H), 7.78-7.97 (dd, 4H), 7.20-7.65(m, 6H), 6.40-6.65 (b, 1H), 5.00-5.55 (b, 1H), 4.13-4.24 (m, 1H),3.68-3.88 (m, 2H), 3.55 (s, 3H), 3.45-3.60 (bt, 2H), 3.30-3.44 (bt, 2H),1.42 (s, 9H).

3-2-(Guanidino)ethylaminocarbonyl!benzoyl-2(S)-phenylsulfonyl-amino-β-alanine(16-7)

A suspension of 16-6 in 6NHCl was stirred at room temperature while theester gradually dissolved over 1 h. After 24 h the reaction was heatedat 50° for 5 h, cooled and filtered. This solid was triturated withEtOAc and filtered to provide the desired acid.

This acid was treated with PCA·HCl as described for 1-8 to provide crudeproduct. This was purified by flash chromatography on silica gel elutingwith EtOH(10)/NH₄ OH(0.5)/H₂ O(0.5) to give 16-7.

¹ H NMR (300 MHz, CD₃ OD) δ 8.24 (s, 1H), 7.77-8.03 (m, 4H), 7.36-7.60(m, 4H), 3.78-3.87 (dd, 1H), 3.50-3.72 (m, 4H), 3.32-3.47 (t, 2H).##STR65## 4-2-(N-(2-Imidazolin-2-yl)amino)ethyloxy!benzoyl-2(S)-phenyl-sulfonylamino-β-alanine(17-1)

A solution of 12-1 (89 mg, 0.2 mmol), 2-methylthio-2-imidazoline·HI (98mg, 0.4 mmol), DIPEA (139 μL, 0.8 mmol) and DMF was stirred at 100° C.for 20 h. Concentration of the cooled reaction mixture followed bychromatography (silica, 9:0.5:0.5 ethanol/NH₄ OH/H₂ O) gave 17-1 as acolorless lyophilozite.

TLC Rf 0.21 (silica, 9:0.5:0.5 ethanol/NH₄ OH/H₂ O);

¹ H NMR (400 MHz, CD₃ OD) δ 7.87 (m, 2H), 7.80 (d, J=9 Hz, 2H), 7.50 (m,3H), 6.98 (d, J=9 Hz, 2H), 4.17 (m, 2H), 3.80-3.50 (m, 5H), 3.73 (bs,4H). ##STR66## 2(S)-Phenylsulfonylamino-3- (4-(N-(imidazolin-2-yl)aminobutyloxy)-phenyl!propionic acid (18-1)

A solution of 6-8 (200 mg, 0.41 mmol), TFA (2 mL), and CH₂ Cl₂ (2 mL)was stirred at ambient temperature for 1.0 h. The solution wasconcentrated and the residual TFA removed azeotropically with toluene.The resulting oil was dissolved in DMF (2 mL) and then treated withDIPEA (211 μL, 1.6 mmol) and 2-methylthio-2imidazoline ·HI (198 mg, 0.82mmol). The resulting solution was heated at 100° C. for 20h.Concentration of the cooled reaction mixture followed by flashchromatography (silica, 10:0.2:0.2→10:1:1 ethanol/NH₄ OH/H₂ O) gave 18-1as a white solid.

TLC Rf 0.38 (silica, 10:1:1 ethanol/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, D₂ O) δ 7.45-7.20 (m, 5H), 6.83 (d, J=9 Hz, 2H), 6.56(d, J=9 Hz, 2H), 3.87 (m, 3H), 3.48 (m, 4H), 3.09 (m, 2H), 2.90 (m, 1H),3.57 (m, 1H), 1.60 (m, 4H). ##STR67## Methyl4-(2-Phthalimidoethyloxy)benzoate (19-2)

A solution of N-(2-hydroxyethyl)phthalimide (Aldrich, 19-1, 6.36 g, 33mmol) and DEAD (5.7 mL, 36 mmol) in 25 mL THF and 10 mL DMF was added toa solution of methyl 4-hydroxybenzoate (1-2, 5.00 g, 33 mmol) and Ph₃ P(9.53 g, 36 mmol) in 100 mL THF during 1 h. After an additional hour thereaction was diluted with ether, washed twice with water, then 1N NaOHand brine, dried (MgSO₄), filtered and concentrated. Flashchromatography (silica gel, CH₂ Cl₂) provided 19-2 as a white solid.

Rf 0.18 (silica, CH₂ Cl₂).

¹ H NMR (300 MHz, CDCl₃) δ 7.95 (d, J=9 Hz, 2H), 7.87 (m, 2H), 7.74 (m,2H), 6.84 (d, J=9 Hz, 2H), 4.28 (t, J=6 Hz, 2H), 4.14 (t, J=6 Hz, 2H),3.87 (s, 3H).

Methyl 4-(2-Aminoethyloxy)benzoate (19-3)

19-2 (1.59 g, 4.89 mmol) was suspended in 25 mL MeOH. Upon addition ofhydrazine (2.0 mL, 64 mmol) the reaction became homogeneous. After 20 ha heavy precipitate had formed. The pH was adjusted to 1 by addition of6N HCl, MeOH evaporated, and the solid suspended in 1N HCl. Afterfiltering through Celite, the filtrate was washed with CH_(2Cl) ₂, thepH was adjusted to 12 with 6N NaOH. The aqueous layer was extracted withfresh CH_(2Cl) ₂. This organic phase was dried (Na₂ SO₄) andconcentrated providing 19-3 as a white solid.

Rf 0.22 (silica, 9:1:1 CH₂ Cl₂ /MeOH/HOAc).

¹ H NMR (300 MHz, CDCl₃) δ 7.99 (d, J=9 Hz, 2H), 6.93 (d, J=9 Hz, 2H),4.04 (t, J=5 Hz, 2H), 3.89 (s, 3H), 3.11 (t, J=5 Hz, 3H), 1.35 (br s,2H).

Methyl 4- 2-(Pyrimidin-2-yl)amino)ethyloxy!benzoate (19-5)

Amine 19-3 (4.30 g, 22 mmol), 19-4 (3.51 g, 22 mmol) and DIPEA (3.8 mL,22 mmol) were heated in 50 mL DMF at 80° for 16 h. The cooled mixturewas concentrated, then diluted with EtOAc, washed with 1N NaOH andbrine, dried (MgSO₄), and concentrated. Flash chromatography (silica,10% acetone/CH₂ Cl₂) provided white crystalline 19-5.

Rf 0.42 (silica, 10% acetone/CH₂ Cl₂).

¹ H NMR (300 MHz, CDCl₃) δ 8.29 (d, J=5 Hz, 2H), 7.99 (d, J=9 Hz, 2H),6.93 (d, J=9 Hz, 2H), 6.57 (t, J=5 Hz, 1H), 5.53 (br m, 1H), 4.20 (t,J=5 Hz, 2H), 3.88 (s, 3H) 3.88 (overlapped t, 2H).

4- 2-(Pyrimidin-2-ylamino)ethyloxy!benzoic acid (19-6)

Pyrimidine ester 19-5 (3.31 g, 12.1 mmol) was combined with 1N NaOH (30mL, 30 mmol) in 50 mL EtOH. After 2 h at 60° the mixture was cooled and30 mL 1N HCl was added (final pH 5). The resulting white precipitate wascollected on a frit, washed with water, and dried providing 19-6.

R_(f) 0.67 (silica, 10:1:1 EtOH/NH₄ OH/H₂ O).

¹ H NMR (300 MHz, DMSO) δ 9.02 (d, J=5 Hz, 2H), 8.60 (d, J=9 Hz, 2H),8.05 (t, J=6 Hz, 1H), 7.76 (d, J=9 Hz, 2H), 7.32 (t, J=5 Hz, 1H), 4.89(t, J=6 Hz, 2H), 4.38 (q, J=6 Hz, 2H), 4.06 (s, 1H).

4-2-(Pyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninetert-butyl ester (19-7)

Acid 19-6 (0.770 g, 2.97 mmol), amine 2-1 (1.0 g, 2.97 mmol), NMM (1.14μL, 10.4 mmol) and HOBT (0.522 g, 3.86 "mmol) were combined in 30 mLDMF, cooled to 0°, and EDC (0.740 g, 3.86 mmol) was added. The mixturewas stirred at RT for 3 days, diluted with ethyl acetate, washed twicewith water, sat. NaHCO₃, and brine, dried (MgSO₄), and concentrated.Flash chromatography (silica, 80% EtOAc/hexanes) provided 19-7 as a waxysolid.

Rf 0.23 (silica, 80% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 8.31 (d, J=5 Hz, 2H), 7.85 (d, J=7 Hz, 2H),7.73 (d, J=9 Hz, 2H), 7.60-7.45 (m, 3H), 6.90 (d, J=9 Hz, 2H), 6.67 (brm, 1H), 6.57 (t, J=5 Hz, 1H), 5.94 (d, J=8 Hz, 1H), 5.68 (br m, 1H),4.17 (t, J=5 Hz, 2H), 4.00-3.83 (m, 4H), 3.59 (m, 1H), 1.28 (s, 9H).

4-2-(Pyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninealanine trifluoroacetate (19-8)

Ester 19-7 (1.05 g, 1.86 mmol) and anisole (0.40 mL, 3.7 mmol) weredissolved in CH₂ Cl₂ (9 mL), cooled to 0°, and TFA (9 mL) was added.After 2 h at 0° and 16 h at 20°, the reaction was concentrated,azeotroped with toluene, and triturated with Et₂ O providing 19-8 as awhite solid.

Rf 0.30 (silica, 22:20:1:1 EtOAc/EtOH/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, CD₃ OD) 8.45 (br, 2H), 7.82 (dt, J=7, 2 Hz, 2H), 7.72(d, J=9 Hz, 2H), 7.50 (tm, J=7 Hz, 1H), 7.42 (tm, J=8 Hz, 2H), 6.99 (d,J=9 Hz, 2H), 6.82 (t, J=5 Hz, 1H), 4.25 (t, J=5 Hz, 2H), 4.18 (dd, J=9,5 Hz, 1H), 3.88 (t, J=5 Hz, 2H), 3.71 (dd, J=14, 5 Hz, 1H), 3.48 (m,1H).

4 -2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-Phenylsulfonylamino-β-alanine(19-9)

Pyrimidine 19-8 (1.05 g, 1.75 mmol) was dissolved in a mixture of aceticacid (50 mL) and conc HCl (4.5 mL). After addition of 10% Pd/C (450 mg)the mixture was shaken on a Parr hydrogenator under 45 psi H₂ pressurefor 2 h. The reaction mixture was filtered, concentrated, azeotropedwith toluene, and purified by flash chromatography (silica 20:1:1 then8:1:1 EtOH/NH₄ OH/H₂ O) providing 19-9 as a white solid.

Rf 0.35 (8:1:1, EtOH/NH₄ OH/H₂ O).

¹ H NMR (300 MHz, CD₃ OD+DCl) δ 7.84 (d m, J=7 Hz, 2H), 7.74 (d, J=9 Hz,2H), 7.50-7.40 (m, 3H), 7.02 (d, J=9 Hz, 2H), 4.22-4.17 (m, 3H), 3.72(dd, J=14, 5 Hz, 1H), 3.60 (t, J=5 Hz, 2H), 3.49 (dd, J=14, 9 Hz, 1H),3.38 (t, J=5 Hz, 4H), 1.95 (qn, J=6 Hz, 2H). ##STR68##Cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-thione (20-2)

A solution of carbon disulfide (1.1 mL, 17.9 mmol) and CH₂ Cl₂ (10 mL)was treated dropwise with cis-1,2-diaminocyclohexane 20-1 (Aldrich) (2.0g, 17.5 mmol) while maintaining the reaction mixture temperature below20° C. with an ice bath. The reaction mixture was stirred at ambienttemperature for 2.0 h after the addition was complete. Concentrationfollowed by refluxing the resulting solid in H₂ O (20 mL) for 20 h gavea yellow solution. The cooled solution was extracted with CH₂ Cl₂ andthe CH₂ Cl₂ portion was dried (MgSO₄) and concentrated. The pale yellowsolid was recrystallized from CH₂ Cl₂ /ether to give 20-2 as a paleyellow solid. mp=164°-166° C.

¹ H NMR (300 MHz, CDCl₃) δ 6.30 (bs, 2H), 3.90 (m, 2H), 1.80-1.30 (m,8H).

2- Cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl!methylsulfide (20-3)

A suspension of, 20-2 (1.3 g, 8.3 mmol) in ethanol (5 mL) at ambienttemperature was treated with iodomethane (0.8 mL, 12.5 mmol). After 20 hthe ethanol was evaporated and the resulting solid triturated withacetone to give 20-3 as a solid.

¹ H NMR (300 MHz, CD₃ OD) δ 4.22 (m, 2H), 2.67 (s, 3H), 2.00-1.40 (m,8H).

4- 2- N-Cis-3a,4,5,6,7,7a-Hexahydro-1H-benzimidazol-2-yl!amino!-ethloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine (20-4)

A solution of 20-3 (298 mg, 1.0 mmol), 12-1 (222 mg, 0.5 mmol), DIPEA(261 μL, 1.5 mmol), H₂ O (6 drops) and DMF (6 mL) was heated at 100° C.for 24 h. The cooled solution was concentrated at 50° C. and the residuechromatographed (silica, 9:0.5:0.5 ethanol/H₂ O/NH₄ OH) to give 20-4 asa colorless solid after lyophilization.

TLC Rf=0.16 (silica, 9:0.5:0.5 ethanol/NH₄ OH/H₂ O);

₁ H NMR (300 MHz, CD₃ OD) δ 7.83 (m, 2H), 7.77 (d, J=9 Hz, 2H), 7.48 (m,3H), 7.01 (d, J=9 Hz, 2H), 4.19 (m, 3H), 3.91 (bs, 2H), 3.75-3.40 (m,4H), 1.90-1.35 (m, 8H). ##STR69## Ethyl 4-(3-oxobut-1-yl )benzoate(21-1)

3-Hydroxy-1-butene (Aldrich) (2.15 mL, 25 mmol), ethyl 4-iodobenzoate(5.52 g, 20 mmol), Et₃ N (3.5 mL, 25 mmol) and Pd(OAc)2 (19 mg, 0.08mmol) were combined in 6 mL CH₃ CN, sealed in a glass pressure tube andheated at 100° for 3 h. The mixture was cooled, diluted with Et₂ O,washed with water, 1N NaOH, 5% KHSO₄, and brine, dried (MgSO₄), andconcentrated. Flash chromatography (silica, 10% EtOAc/hexanes) provided21-1 as a white crystalline solid.

Rf 0.41 (silica, 30% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H),4.36 (q, J=7 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.78 (t, J=7 Hz, 2H), 2.15(s, 3H), 1.38 (t, J=7 Hz, 3H).

Ethyl 4-(4-bromo-3-oxobut-1-yl)benzoate (21-4)

21-1 (3.13 g, 14.2 mmol) was dissolved in EtOH (30 mL) at 0°, and Br₂(805 μL, 15.6 mmol) was added. After warming to RT for 16 h the reactionwas concentrated, diluted with Et₂ O, washed with water and brine, dried(MgSO₄), and concentrated. Flash chromatography (silica, 10%EtOAc/hexane) provided 21-2 as a white solid.

Rf 0.67 (silica, 30% EtOAc/hexane).

¹ H NMR (400 MHz, CDCl₃) δ 7.97 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 2H),4.36 (q, J=7 Hz, 2H), 3.85 (s, 2H), 3.00 (s, 4H), 1.38 (t, J=7 Hz, 3H).

Ethyl 4- 2-(2-aminothiazol-4-yl)ethyl!benzoate (21-3)

Thiourea (374 mg, 4.9 mmol) and 21 -2 (1.4 g, 4.7 mmol) were combined in24 mL EtOH and heated to reflux for 1 h. Concentration and flashchromatography (silica, 80% EtOAc/hexane then 10% MeOH/EtOAc) provided21-3 as a white solid.

Rf 0.54 (silica, EtOAc). ¹ H NMR (300 MHz, DMSO) δ 7.86 (d, J=8 Hz, 2H),7.35 (d, J=8 Hz, 2H), 6.18 (s, 1H), 4.29 (q, J=7 Hz, 2H), 3.4 (br s),2.95 (t, J=7 Hz, 2H), 2.73 (t, J=8 Hz, 2H), 1.31 (t, J=7 Hz, 3H).

4- 2-(2-Aminothiazol-4-yl)ethyl)benzoic acid hydrochloride (21-4)

Ester 21-3 (1.5 g, 5.43 mmol) was treated with 6N HCl for 16 h at RTthen 16 h at 50°. Concentration provided 21-4 as an off-white solid.

Rf 0.74 (silica, 9:1:1 CH₂ Cl₂ /MeOH/HOAc).

¹ H NMR (300 MHz, DMSO) δ 9.45 (br s), 8.10 (d, J=8 Hz, 2H), 7.58 (d,J=8 Hz, 2H), 6.71 (s, 1H), 3.90 (br s), 3.20 (t, J=7 Hz, 2H), 3.07 (t,J=7 Hz, 2H).

4-2-(2-Aminothiazol-4-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-βalaninetert-butyl ester (21-5)

21-4 (150 mg, 0.53 mmol), amine hydrochloride 2-1 (0.53 mmol, 177 mg).HOBT (86 mg, 0.64 mmol), NMM (204 μL, 1.9 mmol), and EDC (122 mg, 0.64mmol) were combined in 2.6 mL DMF at -15°, warmed to RT and stirred for16 h. The reaction was diluted with EtOAc, washed with water, saturatedNaHCO₃ and brine, dried (MgSO₄), and concentrated. Flash chromatography(silica, 70% EtOAc/hexane) provided 21-5 as a clear oil.

Rf 0.48 (silica, EtOAc).

¹ H NMR (300 MHz, CDCl₃) δ 7.86 (d, J=8 Hz, 2H), 7.69 (d, J=8 Hz, 2H),7.60-7.45 (m, 3H), 7.24 (d, J=8 Hz, 2H), 6.70 (br m, 1H), 6.05 (s, 1H),5.90 (br m, 1H), 4.92 (br s, 2H), 3.85-4.00 (m, 2H), 3.62 (m, 1H), 2.99(t, J=8 Hz, 2H), 2.88 (t, J=8 Hz, 2H), 1.29 (s, 9H).

4-2-(2-Aminothiazol-4-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-βalanine(21-6)

Ester 21-5 (200 mg, 0.377 mmol) was dissolved in 2 mL CH₂ Cl₂, and 2 mLTFA was added. After 4 h at RT the mixture was concentrated, azeotropedwith toluene, and purified by flash chromatography (silica, 28:10:1:1EtOAc/EtOH/NH₄ OH/H₂ O) providing 21-6 as a white solid.

Rf 0.39 (silica, 12:10:1:1 EtOAc/EtOH/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, DMSO) δ 8.6 (br s), 7.77 (d, J=8 Hz, 2H), 7.65 (d, J=8Hz, 2H), 7.58 (t, J=7 Hz, 1H), 7.51 (t, J=7 Hz, 2H), 7.27 (d, J=8 Hz,2H), 6.84 (m, 1H), 6.11 (s, 1H), 3.50-3.40 (m, 2H), 3.32 (br s), 2.92(t, J=8 Hz, 2H), 2.70 (t, J=8 Hz, 2H). ##STR70## Benzyl 4-2(S)-(N-BOC-amino)propyloxy!benzoate (22-3)

A THF (25 mL) solution of DIAD (2.9 mL, 14.8 mmol) and 22-1 (Fluka) (2.0g, 11.4 mmol) was added dropwise to a stirred solution of THF (50 mL),22-2 (Fluka) (2.6 g, 11.4 mmol) and Ph₃ P (3.9 g, 14.8 mmol) over a 2 hperiod, followed by heating for 20 h at 70° C. The cooled reactionmixture was concentrated and purified by flash chromatography (silica,20% EtOAc/hexanes) to give 22-3 as a colorless oil.

TLC Rf 0.36 (silica, 5% acetone/CH₂ Cl₂);

¹ H NMR (300 MHz, CDCl₃) δ 8.02 (d, J=9 Hz, 2H), 7.70-7.30 (m, 5H), 6.92(d, J=9 Hz, 2H), 6.45 (m, 1H), 5.33 (s, 2H), 4.75 (m, 1H), 4.06 (m, 1H),3.96 (m, 2H), 1.45 (s, 9H), 1.26 (d, 3H).

4- 2(S)-(N-BOC-Amino)propyloxy!benzoic acid (22-4)

A mixture of 22-3 (1.6 g, 4.3 mmol), 10% Pd/C (0.33 g) and ethanol (25mL) was stirred under a hydrogen atmosphere (1 arm) for 20 h. Filtrationthrough a celite pad followed by concentration of the filtrate gave 22-4as a colorless solid.

¹ H NMR (300 MHz, CDCl₃) δ 8.05 (d, J=9 Hz, 2H), 6.96 (d, J=9 Hz, 2H),4.77 (m, 1H), 4.09 (m, 1H), 3.99 (m, 2H), 1.46 (s, 9H), 1.31 (d, J=7 Hz,3H).

4- 2(S)-(N-BOC-Amino)propyloxy!benzoyl-2(S)-phenylsulfonylaminoβ-alaninetert-butyl ester (22-5)

Following the procedure for coupling 19-6 to 2-1, 22-4 (295 mg, 1.0mmol) was coupled to 2-1 (336 mg, 1.0 mmol) to give 22-5 as a beigesolid.

TLC Rf 0.28 (silica, 10% acetone/CH₂ Cl₂);

¹ H NMR (300 MHz, CDCl₃) δ 7.87 (m, 2H), 7.77 (d, J=9 Hz, 2H), 7.53 (m,3H), 6.93 (d, J=9 Hz, 2H), 6.64 (m, 1H), 5.69 (m, 1H), 4.06 (m, 1H),3.90 (m, 4H), 3.56 (m, 1H), 1.46 (s, 9H), 1.28 (s, 9H).

4-2(S)-Aminopropyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine.multidot.HCl(22-6)

22-5 (545 mg, 0.94 mmol) in 6N HCl (25 mL) and dioxane (25 mL) wasstirred overnight at ambient temperature. Concentration followed bytrituration with ether gave 22-6 as a colorless solid.

TLC Rf 0.62 (silica, 95% ethanol/NH₄ OH);

¹ H NMR (300 MHz, CD₃ OD) δ 7.83 (m, 2H), 7.79 (d, J=9 Hz, 2H), 7.48 (m,3H), 7.08 (d, J=9 Hz, 2H), 4.3-3.3 (m, 6H), 1.43 (d, J=7 Hz, 3H).

4-2(S)-(N-(2-Imidazolin-2-yl)amino)propyloxy!benzoyl-2(S)-phenyl-sulfonylamino-β-alaninetrifluoroacetate (22:7)

A mixture of 22-6 (256 mg, 0.51 mmol), DIPEA (292 μL, 1.7 mmol),(2-methylthio-2-imidazoline·HI) (273 mg, 1.1 mmol) and DMF (2 mL) washeated at 100° C. for 24 h. Concentration followed by flashchromatography (silica, 9:1:1:1 ethanol/NH₄ OH/H₂ O) gave a beige solid.This solid was purified on an HPLC semiprep (C18 column, 95:5 to 5:95 H₂O (0.1% TFA)/CH₃ CN gradient) followed by lyophilization to give 22-7 asa colorless solid.

TLC Rf 0.33 (silica, 9:0.5:0.5 ethanol/H₂ O/NH4OH);

₁ H NMR (300 MHz, CD₃ OD) δ 7.83 (m, 2H), 7.76 (d, J=(9 Hz, 2H), 7.47(m, 3H), 7.00 (d, J=9 Hz, 2H), 4.20-3.40 (m, 6H), 3.73 (m, 4H), 1.37 (d,J=7 Hz, 3H). ##STR71## Methyl 4-(2-bromoethyl)benzoate (23-2)

23-1 (1.95 g, 8.60 mmol) (Aldrich) was suspended in 50 mL MeOH and SOCl₂(5.0 mL, 69 mmol) was added dropwise. Following an exothermic reaction,the mixture was stirred at RT for 16 h, concentrated, and purified byflash filtration (silica, 5% EtOAc/hexanes) providing 23-2 as acolorless oil. Rf 0.37 (silica, 10% EtOAc/hexanes).

¹ H-NMR (300 MHz, CDCl₃) δ8.00 (d, J=8 Hz, 2H), 7.29 (d, J=8 Hz, 2H),3.91 (s, 3H), 3.59 (t, J=7 Hz, 2H), 3.22 (d, J=7 "Hz, 2H).

Methyl 4-(2-cyanoethyl)benzoate (23-3)

Bromide 23-2 (0.52 g, 2.14 mmol) and KCN (167 mg, 2.57 mmol) werecombined in 10 mL DMSO. After 20 h, at RT and 1.5 h at 70° the reactionmixture was diluted with EtOAc, washed with water, sat. NaHCO₃, 10%KHSO₄ and brine, dried (MgSO₄), and concentrated providing 23-3 as ayellow solid. Rf 0.23 (30% EtOAc/hexanes).

¹ H-NMR (300 MHz, CDCl₃) δ 8.02 (d, J=8 Hz, 2H), 7.32 (d, J=9 Hz, 2H),3.92 (s, 3H), 3.02 (t, J=7 Hz, 2H), 2.66 (t, J=7 Hz, 2H).

Methyl 4- 2-(imidazol-2-yl)ethyl!benzoate hydrochloride (23-4)

Nitrile 23-3 (400 mg, 2.11 mmol) was dissolved in 10 mL Et₂ O at 0° MeOH(289 μL, 4.2 mmol) was added, the mixture was saturated with anhydrousHCl. Once the white ppt. formed, the solvent was evaporated and replacedwith MeOH (5 mL), cooled to 0°, and aminoacetaldehyde dimethylacetal(250 μL, 2.3 mmol) was added. The reaction was heated to reflux for 3days then concentrated, diluted in 10 mL 6 N HCl and concentrated againproviding 23-4 as a solid.

Rf 0.16 (silica, 4:1:1 CH₂ Cl₂ /MeOH/HOAc).

^(H-NMR) (400 MHz, D₂ O) δ 7.59 (d, J=7 Hz, 2H), 7.04 (d, J=7 Hz, 2H),6.77 (m, 2H), 3.74 (bs, 2H), 289 (br s, 5H).

4- 2-(Imidazol-2-yl)ethyl!benzoic acid hydrochloride (23 -5)

Ester 23-4 (450 mg; 1.77 mmol) was dissolved in 6N HCl and stirred for16 h. Concentration provided 23-5 as dark oil. Rf 0.28 (silica, 4:1:1CH₂ Cl2/MeOH/HOAc).

¹ H-NMR (400 MHz, DMSO) δ 7.84 (d, J=8 Hz, 2H), 7.51 (s, 2H), 7.32 (d,J=7 Hz, 2H), 3.27 (t, J=7 Hz, 2H), 3.19 (t, J=7, 2H).

4- 2-(Imidazol-2-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alaninetert-butyl ester acetate (23-6)

Acid 23-5 (ca 2 mmol), amine 2-1 (700 mg, 2.0 mmol), HOBT (324 mg, 2.4mmol), and NMM (0.77 mL, 7.0 mmol) were combined in 10 mL DMF at -15°,then EDC (364 mg, 1.9 mmol) was added The mixture was warmed to RT,stirred overnight, then concentrated. Flash chromatography (silica,4:1:1 CH₂ Cl₂ /MeOH/HOAc) provided 23-6, Rf 0.22 (silica, 4:1:1 CH₂ C₂:MeOH:HOAc).

4- 2-(Imidazol-2-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alaninetrifluoroacetate (23-7)

Ester 23-6 (100 mg, 0.2 mmol) was dissolved in 5 mL CH₂ Cl₂, and 5 mLTFA was added. After 1 h the reaction was concentrated and azeotropedwith toluene. Flash chromatography (silica, 50:1:1 EtOH/"NH₄ OH/H₂ O)and preparative HPLC (C₁₈, 0.1% TFA H₂ O/CH₃ CN) provided 23-7.

¹ H-NMR (400 MHz, D₂ O) δ 7.65 (d, J=7 Hz, 2H), 7.39 (d, J=8 Hz, 2H),7.28-7.20 (m, 3H), 7.15 (s, 2H), 7.11 (d, J=9 Hz, 2H), 3.91 (dd, J=10, 4Hz, 1H), 3.60 (dd, J=14, 4 Hz, 1H), 3.32 (dd, J=:14, 10 Hz, 1H), 3.23(t, J=7 Hz, 2H), 3.06 (t, J=7 Hz, 2H). ##STR72## Methyl4-(t-butyloxyacetyloxy)benzoate (24-1)

t-Butyl bromoacetate (0.83 mL, 5.1 mmol), methyl 4-hydroxybenzoate (780mg, 5.1 mmol) and Cs₂ CO₃ (1.83 g, 5.6 mmol) were combined in 25 mL DMF.After 16 h, the reaction was diluted with ethyl acetate, washed withwater, saturated NaHCO₃, 10% KHSO₄ and brine, dried (MgSO₄) andconcentrated providing 24-1 as a yellow oil. Rf 0.84 (silica, 50%EtOAC/hexane).

¹ H-NMR (300 MHz, CDCl₃) δ 7.96 (d, J=8 Hz, 2H), 6.88 (d, J=8 Hz, 2H),4.55 (s, 2H), 3.86 (s, 3H), 1.46 (s, 9H).

Methyl 4-(carboxymethyloxy)benzoate (24-2)

Ester 24-1 was dissolved in 15 mL CH₂ Cl₂, then 15 mL TFA was added.After 2 h, the mixture was concentrated providing 24-2 as a white solid.

¹ H-NMR (300 MHz, DMSO) δ 7.91 (d, J=9 Hz, 2H), 7.03 (d, J=9 Hz, 2H),4.79 (s, 2H), 3.82 (s, 3H).

Methyl 4- (thiazol-2-ylamino)acetyloxy!benzoate (24-3)

Acid 24-2 (1.0 g, 5 mmol) was suspended in 25 mL benzene, a few drops ofDMF were added, then oxalyl chloride (1.3 ml, 15 mmol) in two portions.Once the gas evolution stopped, the homogeneous solution wasconcentrated, diluted with 25 mL DMF, and treated with 2-aminothiazole(550 mg, 5.5 mmol) and DIPEA (1 mL, 5.7 mmol). This mixture was stirredfor 16 h, diluted with EtOAc, washed with water, sat. NaHCO₃, and brine,dried (MgSO₄) and concentrated providing 24-3 as an orange solid.

¹ H-NMR (400 MHz, CDCl₃) δ 8.06 (d, J=9 Hz, 2H), 7.50 (d, J=4 Hz, 1H),7.05 (d, J=4 Hz, 1H), 7.00 (d, J=9 Hz), 4.80 (s, 2H), 3.91 (s, 3H).

Methyl 4- 2-(thiazol-2-ylamino)ethyloxy!benzoate (24-4)

Amide 24-3 (1.0 g, 3.4 mmol) was dissolved in 7 mL toluene at 0°, andBH₃ ·DMS (341 μL, 3.6 mmol) was added. After 15 min, the reaction washeated to reflux for 16 h, cooled to 0°, and quenched with 10% Na₂ CO₃.The mixture was extracted with EtOAc, the organic phase was washed withwater and brine, dried (MgSO₄), concentrated, and purified by flashchromatography (silica, 70% EtOAc/hexane) providing 24-4 as a whitesolid. Rf 0.64 (silica, EtOAc).

¹ H-NMR (400 MHz, CDCl₃) δ 7.99 (d, J=9 Hz, 2H), 7.14 (d, J=4 Hz, 1H),6.92 (d, J=9 Hz, 2H), 6.53 (d, J=4 Hz, 1H), 4.24 (t, J=5 Hz, 2H), 3.89(s, 3H), 3.79 (q, J=5 Hz, 2H).

4- 2-(Thiazol-2-ylarnino)ethyloxy!benzoic acid hydrochloride (24-5)

Ester 24-4 (180 mg, 0.65 mmol) was heated at 50° in 6 mL 6 N HCl for 16h, then concentrated providing 24-5 as a yellow solid.

Rf 0.68 (silica, 9:1:1 CH₂ Cl₂ /MeOH/HOAc).

¹ H-NMR (300 MHz, CD₃ OD) δ 7.96 (d, J=9 Hz, 2H), 7.30 (d, J=4 Hz, 1H),7.00 (d, J=9 Hz, 2H), 6.97 (d, J=4 Hz, 1H), 4.34 (t, J=5 Hz, 2H), 3.89(t, J=5 Hz, 2H).

4-2-(Thiazol-2-ylamino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-βalaninetert-butyl ester (24-6)

Acid 24-5 (160 mg, 0.60 mmol), amine 2-1 (215 mg, 0.60 mmol), EDC (140mg, 0.73 mmol), HOBT (98 mg, 0.73 mmol), and NMM (235 μL, 2.1 mmol) werecombined in 3 mL DMF at -15°. After stirring at RT for 16 h, thereaction was diluted with EtOAc, washed with water, sat. NaHCO₃ andbrine, dried, concentrated, and purified by flash chromatography(silica, 70% EtOAc/hexane) providing 24-6 as an off-white solid. Rf 0.54(silica, EtOAc).

¹ H-NMR (400 MHz, CDCl₃) δ 7.86 (d, J=8 Hz, 2H), 7.76 (d, J=9 Hz, 2H),7.57 (t, J=8 Hz, 1H), 7.50 (t, J=8 Hz, 2H), 7.14 (d, J=4 Hz, 1H), 6.92(d, J=9 Hz, 2H), 6.70 (br m, 1 H), 6.53 (d, J=4 Hz, 1H), 4.21 (t, J=5Hz, 2H), 3.95-3.85 (m, 2H), 3.77 (t, J=5Hz, 2H), 3.58 (m, 1H), 1.28 (s,9H).

4- 2-(Thiazol-2-ylamino)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine (24-7)

Ester 24-6 (197 mg, 0.36 mmol) was dissolved in 1.8 mL CH₂ Cl₂ andtreated with 1.8 mL TFA. Once the starting material had disappeared, thereaction was concentrated, and flash chromatography (silica, 18:10:1:1EtOAc/EtOH/NH₄ OH/H₂ O) provided 24-7 as a white solid. Rf 0.26 (silica,18:10:1:1 EtOAc/EtOH/NH₄ OH/H₂ O).

¹ H-NMR (400 MHz, D₂ O) δ 7.52 (dd, J=8, 2 Hz, 2H), 7.41 (d, J=9 Hz,2H), 7.10-7.04 (m, 3H), 6.93 (d, J=4 Hz, 1H), 6.89 (d, J=9 Hz, 2H), 6.53(d, J=4 Hz, 1H), 4.21 (t, J=5 Hz, 2H), 3.60 (t, J=5 Hz, 2H), 3.55-3.44(m, 2H), 3.06 (dd, J=13, 9 Hz, 1H). ##STR73## tert-Butyl2(S)-Benzyloxycarbonylamino-3-aminopropionate hydrochloride (25-a)

Following the procedure for converting 2-1b to 2-1,3-amino-2(S)-benzyloxycarbonylaminopropionic acid (230 mg, 1.0 mmol;Fluka) gave 25-a as a white solid.

¹ H NMR (300 MHz, D₂ O) δ 7.45 (br s, 5H), 5.18 (s, 2H), 4.35 (m, 1H),3.35 (m, 1H), 3.05 (m, 1H), 1.45 (s, 9H).

4-2-(Pyrimidin-2-ylarnino)ethyloxy!benzoyl-2(S)-benzyloxycarbonyl-amino-.beta.-alaninetert-butyl ester (25-1)

To a stirred solution of 19-6 (400 mg, 1.5 mmol), 25-a (538, 1.6 mmol),DMF (10 mL), and NMM (6.27 mg, 6.0 mmol) at ambient temperature wasadded BOP reagent (717 mg, 1.6 mmol). After 24 h, the reaction mixturewas diluted with EtOAc and then washed with H₂ O and brine, dried(MgSO₄) and concentrated. Flash chromatograpy (silica, 60%EtOAc/hexanes) gave 25-1 as a yellow oil.

TLC Rf 0.14 (silica, 60% EtOAc/hexanes);

¹ H NMR (300 MHz, CD₃ OD) δ 8.22 (m, 2H), 7.68 (m, 2H), 7.24 (m, 5H),6.92 (m, 2H), 6.06 (m, 1H), 5.00 (m, 2H), 4.30 (m, 1H), 4.13 (m, 5H),3.72 (m, 2H), 3.67 (m, 2H), 1.32 (s, 9H).

4-2-(Pyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-benzyloxycarbonyl-amino-.beta.-alanine(25-2)

A solution of 25-1 (840 mg, 1.6 mmol) and CH₂ Cl₂ (10 ml) at ambienttemperature was treated with TFA (10 ml). After stirring for 4.0 h, thereaction mixture was concentrated and the residual TFA removedazeotropically with toluene. Trituration of the resulting waxy solidwith ether provided 25-2 as a white solid.

¹ H NMR (300 MHz, CD₃ OD) δ 8.41 (m, 2H), 7.67 (m, 2H), 7.22 (m, 5H),6.91 (m, 2H), 6.82 (m, 2H), 4.98 (m, 2H), 4.38 (m, 1H), 4.20 (m, 2H),3.83 (m, 2H), 3.72 (m, 1H), 3.62 (m, 1H).

4-2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-amino-.beta.-alanine(25-3)

A mixture of 25-2 (500 mg, 1.0 mmol), conc. HCl (6 mL), AcOH (30 mL) and10% Pd/C (300 mg) was shaken on a Parr apparatus under a hydrogenatmosphere (70 psi) at ambient temperature for 3.0 h. The mixture wasthen filtered through a celite pad, the filtrate concentrated and theresidual AcOH removed azeotropically with toluene. The residue wastriturated with 8:1:1 ethanol/NH₄ OH/H₂ O. The solid was collected byfiltration, washed with ether and dried in vacuo to give 25-3 as ayellow solid. TLC Rf 0.17 (silica, 8:1:1 ethanol/NH₄ OH/H₂ O);

¹ H NMR (300 MHz, CD₃ OD) δ 7.84 (d, J=9 Hz, 2H), 7.02 (d, J=9 Hz, 2H),4.22 (m, 1H), 4.12 (m, 2H), 4.00-3.30 (m, 8H), 1.92 (m, 2H).

4-2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-benzyloxycarbonylamino-β-alanine(25-5)

A stirred solution of 25-3 (360 mg, 1.0 mmol), dioxane (5 mL), H₂ O (5mL) and NMM (453 μL, 4.0 mmol) at ambient temperature was treated with25-4 (Aldrich) (257 mg, 1.0 mmol). After 1.0 h the solution wasconcentrated. Flash chromatography (silica, 10:1:1 ethanol/NH₄ OH/H₂ O)gave 25-5 as a white solid. TLC Rf 0.34 (silica, 10:1:1 ethanol/NH₄OH/H₂ O);

¹ H NMR (300 MHz, DCl/CD₃ OD) δ 7.80 (d, J=9 Hz, 2H), 7.31 (m, 5H), 7.02(d, J=9 Hz, 2H), 5.07 (m, 2H), 4.50 (m, 1H), 4.19 (m, 2H), 3.77 (m, 2H),3.62 (m, 2H), 3.38 (m, 4H), 1.97 (m, 2H). ##STR74##

Methyl 2(S)-benzoylamino-3- 4-(4-N-Boc-aminobutyloxy)phenyl!propionate(26-1)

A solution of 6-6 (600 mg, 1.6 mmol), pyridine (265 μL, 3.3 mmol) andCH₂ Cl₂ (10 mL) at ambient temperature was treated with benzoyl chloride(228 μL, 2.0 mmol). After 24 h the solution was diluted with EtOAc andwashed with H₂ O, sat. NaHCO₃, 10% KHSO₄ and brine, dried (MgSO₄) andconcentrated. Flash chromatography (silica, 30% EtOAc/hexanes) gave 26-1as a white solid.

TLC Rf 0.15 (silica, 30% EtOAc/hexanes);

¹ H NMR (300 MHz, CD₃ OD) δ 7.65 (m, 2H), 7.39 (m, 3H), 7.07 (m, 3H),6.76 (m, 2H), 4.05 (m, 1H), 3.88 (m, 2H), 3.66 (s, 3H), 3.20-2.90 (m,4H), 1.80-1.50 (m, 4H), 1.39 (s, 9h).

Methyl 2(S)-benzoylamino-3-4-(4-pyrimidin-2-ylaminobutyloxy)phenyl!propionate (26-2)

A solution of 26-1 (375 mg, 0.8 mmol), CH₂ Cl₂ (4 mL) and TFA (4 mL) wasstirred at ambient temperature for 2.0 h. The solution was concentratedand the residual TFA removed azeotropically with toluene. The residuewas dissolved in DMF (4 mL) then treated sequentially with DIPEA (414μL, 3.2 mmol) and 2-bromopyrimidine (152 mg, 0.95 mmol) and then heatedat 80° C. for 20 h. The cooled reaction mixture was diluted with EtOAcand then washed with H₂ O and brine, dried (MgSO₄) and concentrated.Flash chromatography (silica, 50% to 80% EtOAc/hexanes) gave 26-2 as abrown oil. TLC Rf 0.34 (silica, 80% EtOAc/hexanes);

¹ H NMR (300 MHz, CD₃ OD) δ 8.17 (m, 2H), 7.68 (d, J=9 Hz, 2H), 7.40 (m,3H), 7.09 (m, 2H), 6.76 (d, J=9 Hz, 2H), 6.49 (m, 1H), 4.05 (m, 1H),3.90 (m, 3H), 3.68 (s, 3H), 3.40, 2.90 (m, 4"H), 1.72 (m, 4H).

2(S)-Benzoylamino-3- 4-(4-pyrimidin-2-ylaminobutyloxy)phenyl!propionicacid hydrochloride (26-3)

A solution of 26-2 (250 mg, 0.56 mmol), in 6N HCl (6 mL) was heated at60° C. for 2.0 h. The solution was concentrated to give 26-3 as a solid,which was used directly in the next step.

2(S)-Benzoylamino-3 -4-(4-(3,4,5,6-tetrahydropyrimidin-2-ylamino)butyloxy)phenyl!propionicacid (26-4)

A mixture of 26-3 (250 mg, 0.56 mmol), AcOH (20 mL), conc. HCl (3 mL)and 10% Pd/C (150 mg) was shaken on the Parr apparatus (60 psi) atambient temperature for 2.5 h. The reaction mixture was then filteredthrough a celite pad and the filtrate concentrated. Flash chromatography(silica, 10:1:1 to 9:1:1 ethanol/NH₄ OH/H₂ O) gave 26-4 as a whitesolid.

TLC Rf (silica, 9:1:1 ethanol/NH₄ OH/H₂ O);

¹ H NMR (400 MHz, CD₃ OD) δ 7.78 (m, 2H), 7.60-7.40 (m, 3H), 7.17 (d,J=9 Hz, 2H), 6.79 (d, J=9 Hz, 2H), 4.70 (m, 1H), 3.96 (m, 2H), 3.33(m,4H), 3.30 (m, 1H), 3.16 (m, 2H), 3.11 (m, 1H), 1.95 (m, 2H), 1.80##STR75## 4-2-(Pyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-(N-methyl)-phenylsulfonylamino-β-alaninetert-butyl ester (27-1)

A solution of 19-7 (190 mg, 0.35 mmol), CH₃ OH (28 μL, 0.7 mmol), Ph₃ P(101 mg, 0.39 mmol), DIAD (758 μL, 0.9 mmol) and THF (10 mL) was stirredfor 24 h at ambient temperature. The reaction mixture was then dilutedwith EtOAc and washed with H₂ O and brine, dried (MgSO₄) andconcentrated. Flash chromatography (silica, CHCl₃ saturated with NH₃)gave crude 27-1 as a gum.

TLC Rf=0.21 (silica, 20% acetone/CH₂ Cl₂);

¹ H NMR (300 MHz, CDCl₃) δ 8.29 (d, J=5 Hz, 1H), 7.90-7.40 (m, 10H),6.90 (d, J=9 Hz, 2H), 6.57 (m, 1H), 4.72 (m, 1H), 4.19 (m, 2H), 3.87 (m,2H), 2.90 (s, 3H), 1.30 (s, 9H).

4-2-(Pyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-(N-methyl)-phenylsulfonylamino-β-alanine(27-2)

A solution of 27-1 (190 mg, 0.35 mmol), TFA (4 mL) and CH₂ Cl₂ (8 mL)was stirred at ambient temperature for 4 h. The reaction wasconcentrated and the residual TFA removed azeotropically with toluene.Flash chromatography (silica, 95/2.5/2.5 CH₂ Cl₂ /CH₃ OH/AcOH) gave 27-2as a colorless foam.

TLC Rf=0.26 (silica, 9:0.5:0.5 CH₂ Cl₂ /CH₃ OH/AcOH);

¹ H NMR (300 MHz, CD₃ OD) δ 8.30 (d, J=5 Hz, 2H), 7.74 (d, J=11 Hz, 2H),7.71 (d, J=9 Hz, 2H), 7.45-7.25 (m, 3H), 6.99 (d, J=9 Hz, 2H), 6.62 (m,1H), 5.80 (m, 1H), 4.21 (m, 2H), 3.90 (m, 1H), 3.79 (m, 2H), 3.60 (m,1H), 2.89 (s, 3H).

4-2-(3,4,5,6-Tetrahydropyrimidin-2-ylamino)ethyloxy!benzoyl-2(S)-(N-methyl)phenylsulfonylamino-β-alanine(27-3)

A mixture of 27-2 (190 mg, 0.35 mmol), HOAc (10 mL), conc. HCl (0.6 mL)and 10% Pd/C (38 mg) was shaken on the Parr apparatus (40 psi) atambient temperature for 2.0 h. The reaction mixture was filtered througha celite pad and the filtrate concentrated. Flash chromatography(silica, ethanol/NH₄ OH/H₂ O 9:0.5:0.5) gave 27-3 as a colorlesslyophilizate.

TLC Rf 0.34 (silica, 8:1:1 ethanol/NH₄ OH/H₂ O);

¹ H NMR (300 MHz, CDCl₃) δ 7.80 (m, 4H), 7.55-7.35 (m, 3H), 7.02 (d, J=9Hz, 2H), 7.02 (d, J=9 Hz, 2H), 4.95 (m, 1H), 4.20 (m, 2H), 3.86 (m, 1H),3.69 (m, 1H), 3.59 (m, 2H), 3.38 (m, 4H), 2.88 (s, 3H), 1.95 (m, 2H)##STR76## (5,6-Dihydro-4-keto-(1H)-pyrimidin-2-yl)methylsulfide (28-2)

A suspension of 28-1 (1.98 g, 15.2 mmol) in THF (40 mL) was treated withiodomethane and stirred at ambient temperature for 60 h. Theheterogeneous reaction mixture was then filtered to give 28-2 as acolorless crystalline solid m.p.=205° C. (D).

¹ H NMR (300 MHz, CD₃ OD) δ 3.90 (t, J=7 Hz, 2H), 2.91 (t, J=7 Hz, 2H),2.77 (s, 3H).

4-2-(N-(5,6-Dihydro-4-keto-1(H)-pyrimidin-2-yl)amino)ethyloxy!-benzoyl-2(S)-phenylsulfonylamino-β-alanine(28-3)

A solution of 28-2 (272 mg, 1.0 mmol), 12-1 (222 mg, 0.5 mmol), DIPEA(261 μL, 1.5 mmol) and DMF (5 mL) was heated at 100° C. for 20 h. Thecool reaction mixture was concentrated.

Flash chromatography (silica, 95% ethanol/NH₄ OH) and preparative HPLC(C18, 0.1% TFA in H₂ O/CH₃ CN) provided pure 28-3 as a colorless solidafter lyophilization.

TLC Rf 0.58 (silica, 95% ethanol/NH₄ OH);

¹ H NMR (300 MHz, CD₃ OD) δ 7.83 (d, J=7 Hz, 2H), 7.78 (d, J=9 Hz, 2H),7.48 (m, 3H), 7.02 (d, J=9 Hz, 2H), 4.26 (m, 2H), 4.20 (m, 1H),3.80-3.60 (m, 4H), 3.48 (m, 1H), 2.76 (t, J=7 Hz, 2H). ##STR77## Ethyl4-(trimethylsilylethynyl)benzoate (29-1)

TMS-acetylene (Aldrich) (5.0 mL, 35.5 mmol), ethyl 4-bromobenzoate (58mL, 35.5 mmol) and Et₃ N (20 mL, 144 mmol) were combined in 50 mL CH₃ CNin a glass pressure tube. (Ph₃ P)₂ PdCl₂ (198 mg, 0.28 mmol) and CuI(100 mg, 0.53 mmol) were added, and the reaction was sealed and heatedat 100° for 18 h. Dilution with EtOAc, washing twice with water, thenbrine, drying and concentration provided 29-1 as a brown liquid.

Rf 0.60 (silica, 10% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 7.97 (d, J=8 Hz, 2H), 7.51 (d, J=9 Hz, 2H),4.37 (q, J=7 Hz, 2H), 1.40 (t, J=7 Hz, 3H), 0.26 (s, 9H).

Ethyl-4-ethynylbenzoate (29-2)

Silylacetylene 29-1 (9.40 g, 38 mmol) was dissolved in 100 mL EtOH, K₂CO₃ (0.25 g 1.8 mmol) was added and the mixture was stirred for 16 h,concentrated, and purified by flash chromatography (silica, 5% Et₂O/hexane) provided 29-2 as a yellow oil.

Rf 0.47 (silica, 10% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 8.00 (d, J=8 Hz, 2H), 7.55 (d, J=8 Hz, 2H),4.38 (q, J=7 Hz, 2H), 3.22 (s, 1H), 1.40 (t, J=7 Hz, 3H).

Ethyl 4-(2-aminopyridin-6-ylethynyl)benzoate (29-3)

2-Amino-6-bromopyridine (0.38 g, 2.4 mmol), alkyne 29-2 (0.35 g, 2.0mmol), Et₃ N (1.0 mL, 7.2 mmol), (Ph₃ P)₂ PdCl₂ (76 mg, 0.11 mmol), anCuI (26 mg, 0.14 mmol) were combined in 5 mL CH₃ CN, sealed in a glasspressure tube and heated to 100° for 3 h. The mixture was diluted withEtOAc, washed with water and brine, dried (MgSO₄), concentrated, andpurified by flash chromatography (silica, 5% acetone/hexane), to give29-3 as a tan solid.

Rf 0.45 (silica, 10% acetone/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 8.03 (d, J=8 Hz, 2H), 7.64 (d, J=8 Hz, 2H),7.44 (t, J=8 Hz, 1H), 6.95 (d, J=7 Hz, 1H), 6.50 (d, J=8 Hz, 1H), 4.55(br s, 2H), 4.39 (q, J=7 Hz, 2H), 1.40 (t, J=7 Hz, 3H).

4-(2-Aminopyridin-6-ylethynyl)benzoic acid (29-4)

Ester 29-3 (300 mg, 1.13 mmol) and 1N NaOH (2.8 mL, 2.8 mmol) werecombined in 6 mL EtOH. After 16 h the mixture was concentrated, EtOAcwas added, and water and 10% KHSO₄ were added to pH 7. The resultingprecipitate was collected, the organic phase was washed with brine,dried and concentrated. Both fractions contained 29-4, an orange/yellowsolid.

Rf 0.50 (silica, 18:1:1 CH₂ Cl₂ /MeOH/HOAc).

¹ H NMR (400 MHz, CD₃ OD+NaOD) δ 7.95 (d, J=9 Hz, 2H), 7.53 (d, J=9 Hz,2H), 7.46 (dd, J=9,7 Hz, 1H), 6.84 (dd, J=7,1 Hz, 1H), 6.58 (dd, J=8,1Hz, 1H).

4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonyl-amino-β-alaninet-butyl ester(29-5)

Acid 29-4 (234 mg, 0.98 mmol), amine 2-1 (351 mg, 0.98 mmol), EDC (225mg, 1.2 mmol), HOBT (159 mg, 1.2 mmol) and NMM (323 μL, 2.9 mmol) werecombined in 5 mL DMF. After 16 h the mixture was diluted with EtOAc,washed with water, sat. NaHCO₃ and brine, dried (MgSO₄), concentratedand chromatographed (silica, 80% EtOAc/hexane) providing 29-5.

Rf 0.53 (EtOAc, silica).

¹ H NMR (300 MHz, CDCl₃) δ 7.86 (d, J=8 Hz, 2H), 7.76 (d, J=9 Hz, 2H),7.62 (d, J=9 Hz, 2H), 7.57-7.41 (m, 4H), 6.95 (dd, J=7,1 Hz, 1H), 6.86(br m, 1H) 6.50 (dd, J=8, 1H, 1H), 5.92 (br m, 1H), 458 (br s, 2H),4.00-3.84 (m, 2H), 3.62 (m, 1H), 1.29 (s, 9H).

4-(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonylamino-β-alanine(29-6)

Ester 29-5 (375 mg, 0.72 mmol), was dissolved in 3.6 mL CH₂ Cl₂ /3.6 mLTFA. After 2 h the reaction was concentrated, azeotroped with toluene,and triturated with 10:1:1 EtOH/NH₄ OH/H₂ O, providing 29-6 as a lightyellow solid.

¹ H NMR (400 MHz, D₂ O+NaOD) δ 7.55-7.45 (m, 4H), 7.45-7.36 (m, 3H),7.10-7.05 (m, 3H), 6.86 (m, 1H), 6.54 (m, 1H), 3.54-3.42 (m, 2H), 3.04(m, 1H).

4-2-(2-Aminopyridin-6-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine(29-7)

Alkyne 29-6 (60 mg, 0.13 mmol), was suspended in 1.3 mL H₂ O, 1 N NaOHwas added until the mixture was homogeneous, 10% Pd/C (12 mg) was added,and an H₂ balloon was applied. After 16 h the reaction was filtered,concentrated, and purified by flash chromatography (silica, 12:10:1:1EtOAc/EtOH/NH₄ OH/H₂ O) providing 29-7 as a white solid.

¹ H NMR (300 MHz, D₂ O+NaOD) δ 7.73 (d, J=8 Hz, 2H), 7.52 (d, J=9 Hz,2H), 7.34 (d, J=8 Hz, 2H), 7.30-7.15 (m, 3H), 6.67 (d, J=7 Hz, 1H), 6.62(d, J=8 Hz, 1H), 3.80-3.68 (m, 2H), 3.35-3.05 (m, 5H). ##STR78## Ethyl2-Chloropyridin-6-ylacetate (30-1)

LDA (69 mmol) was prepared in 50 mL THF, cooled to -78°, and6-chloro-2-picoline (Aldrich) (3.7 mL, 34 mmol) was added dropwise,forming a precipitate. After 15 min, diethylcarbonate (4.9 mL, 41 mmol)was added, the burgtmdy solution was stirred at -78° for 15 min morethen quenched with sat. NH₄ Cl. The mixture was warmed to RT, extractedtwice with EtOAc, the organic layers were washed with brine, dried(MgSO₄), and concentrated. Flash chromatography (silica, 10%EtOAc/hexane) provided 30-1 as a yellow oil.

Rf 0.41 (silica, 20% EtOAc/hexane).

¹ H NMR (400 MHz, CDCl₃) δ 7.64 (d, J=8 Hz, 1H), 7.27-7.24 (m, 2H), 4.19(q, J=7 Hz, 2H), 3.83 (s, 2H), 1.27 (t, J=7 Hz, 3H).

2-(2-Chloropyridin-6-yl)ethanol (30-2)

Ester 30-1 (1.34 g, 6.7 mmol) was dissolved in 10 mL CH₂ Cl₂ at -78°,DIBAL (1 M in CH₂ Cl₂, 17 mL, 17 mmol) was added, the mixture was warmedto RT for 15 min before quenching in a mixture of 25 mL saturatedaqueous Na--K tartrate and 100 mL EtOAc. This mixture was shakenvigorously. The phases were allowed to separate, and the organic layerwas washed with brine, dried (MgSO₄), concentrated and chromatographed(silica, 40% EtOAc/hexane), providing 30-2 as a yellow oil.

Rf 0.26 (silica, 50% EtOAc/hexane).

¹ H NMR (400 MHz, CDCl₃) δ 7.59 (t, J=8 Hz, 1H), 7.20 (t, J=8 Hz, 1H),7.12 (d, J=8 Hz, 1H), 4.02 (q, J=6 Hz, 2H), 3.10 (t, J=6 Hz, 1H), 3.01(t, J=5 Hz, 2H).

2- 2-(4-Methoxybenzylamino)pyridin-6-yl!ethanol (30-3)

Chloropyridine 30-2 (150 mg, 0.95 mmol) and 4-methoxybenzylamine (4 mL,31 mmol) were combined neat and heated in a sealed tube at 160° for 4days. After diluting with EtOAc and water the pH was adjusted to 7phases separated and the organic phase was washed with brine, dried(MgSO₄) and concentrated. Flash chromatography (twice on silica, 50% and40% EtOAc/hexane) provided 30-3 as a yellow semi-solid.

Rf 0.38 (silica, 50% EtOAc/hexane).

¹ H NMR (400 MHz, CDCl₃) δ 7.34 (t, J=8 Hz, 1H), 7.29-7.23 (m, 3H),6.90-6.85 (m 3H), 6.43 (d, J=7 Hz, 1H), 6.26 (d, J=8 Hz, 1H), 4.76 (brm, 1H), 4.39 (d, J=6 Hz, 2H), 3.95 (t, J=5 Hz, 2H), 3.80 (s, 3H), 2.84(t, J=5 Hz, 2H).

Methyl 4- 2-(4-methoxybenzylamino)pyridin-6-yl)ethyloxy!benzoate (30-4)

Methyl 4-hydroxybenzoate (68 mg, 0.45 mmol) and Ph₃ P (175 mg, 0.67mmol) were dissolved in 5 mL THF. A solution of 30-3 (115 mg, 0.44 mmol)and DIAD (123 μL, 0.62 mmol) in THF was slowly added. After 1 h thereaction was concentrated and purified by flash chromatography (silica,20% EtOAc/hexane) providing 30-4 as an off-white solid.

Rf 0.64 (silica, 50% EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 7.96 (d, J=9 Hz, 2H), 7.36 (t, J=8 Hz, 1H),7.28-7.24 (m, 2H), 6.93-6.83 (m, 4H), 6.55 (d, J=7 Hz, 1H), 6.25 (d, J=8Hz, 1H), 4.41-4.34 (m, 4H), 3.88 (s, 3H), 3.79 (s, 3H), 3.10 (t, J=7 Hz,2H).

4- 2-(2-Aminopyridin-6-yl)ethyloxy)benzoic acid acetate (30-5)

Ester 30-4 (240 mg, 0.61 mmol) was dissolved in 6N HCl and heated at 50°for 16 h. Concentration and flash chromatography (silica, 18:1:1 CH₂ Cl₂/MeOH/HOAc)provided 30-5 as a light orange solid.

Rf 0.19 (silica, 18:1:1 CH₂ Cl₂ /MeOH/HOAc).

¹ H NMR (300 MHz, DMSO) δ 7.88 (d, J=8 Hz, 2H), 7.29 (t, J=8 Hz, 1H),6.90 (d, J=8 Hz, 2H), 6.45 (d, J=7 Hz, 1H), 6.29 (d, J=8 Hz, 1H), 4.30(t, J=7 Hz, 2H), 2.94 (t, J=6 Hz, 2H), 1.83 (s).

4-2-(2-Aminopyridin-6-yl)ethyloxy)benzoyl-.2(S)-phenylsulfonyl-amino-.beta.-alaninet-butyl ester (30-6)

Acid 30-5 (100 mg, 0.31 mmol), amine 2-1 (210 mg, 0.59 mmol), EDC (90mg, 0.47 mmol), HOBT (63 mg, 0.47 mmol) and NMM (150 μL, 1.4 mmol) werecombined in 2 mL DMF at -15°. After warming to RT for 16 h the mixturewas concentrated and chromatographed (silica, 9:1:1 CH₂ Cl₂ /MeOH/HOAc),providing 30-6.

Rf 0.32 (silica, 9:1:1 CH₂ Cl₂ /MeOH/HOAc).

4-2-(2-Aminopyridin-6-yl)ethyloxy!benzoyl-2(S)-phenylsulfonyl-amino-β-alanine(30-7)

Ester 30-6 (120 mg, 0.22 mmol) was dissolved in 1 mL CH₂ Cl₂, and 1 mLTFA was added. After 1 h the reaction was concentrated azeotroped withtoluene, chromatographed (silica, 18:1:1→9:1:1→CH₂ Cl₂ /MeOH/HOAc) andpurified by prep HPLC (C₁₈, 0.1% TFA in H₂ O/CH₃ CN) providing 30-7 as awhite solid.

Rf 0.33 (silica, 4:1:1 CH₂ Cl₂ /MeOH/HOAc).

¹ H NMR (400 MHz, D₂ O) δ 7.46 (d, J=7 Hz, 2H), 7.36-7.29 (m, 3H),7.02-6.95 (m, 3H), 6.79 (d, J=8 Hz, 2H), 6.57 (d, J=8 Hz, 1H), 6.39 (d,J=8 Hz, 1H), 4.28 (t, J=7 Hz, 2H), 3.50-3.40 (m, 2H), 2.98 (m, 1H), 2.91(t, J=5 Hz, 2H). ##STR79## 4- 2-(1H-Imidazo4,5-b!pyridin-2-yl)ethenyl!benzoic acid (31-3)

A solution of 31-1 (546 mg, 5.0 mmol), (Aldrich) 3-2 (1030 mg, 5.0 mmol)(Chem. Pharm. Bull. 36(2), 495(1988)) and PPA (20 mL) was heated at 100°C. for 3 h. After cooling, the reaction was poured into ice water andthe yellow solid collected by filtration and added to 1N NaOH (50 mL).After stirring under ambient conditions for 18 h, the reaction wasacidified with 12N HCl to provide 31-3 as a yellow solid.

¹ H NMR (400 MHz, d₆ -DMSO) δ 8.54 (m, 1H), 8.25 (m, 1H), 8.10 (d, J=8Hz, 2H), 8.02 (d, J=16 Hz, 1H), 7.93 (d, J=8 Hz, 2H), 7.46-7.54 (m, 2H).##STR80## 4- 2-(1H-Imidazo4,5-b!pyridin-2-yl)ethenyl!benzoyl-2(S)-phenyl-sulfonylamino-β-alaninet-butyl ester (31-4)

A DMF solution (10 mL) containing 31-3 (301 mg, 1.0 mmol) 2-1 (336 mg,1.0 mmol), HOBT (206 mg, 1.35 mmol), EDC (258 mg, 1.35 mmol) and NMM(440 μl, 4.0 mmol) was stirred under ambient conditions for 18 h. TheDMF was evaporated and the residue partitioned between CH₂ Cl₂ and H₂ O.The organic layer was dried (MgSO₄) and concentrated to a yellow gumwhich was purified by flash chromatography (silica, 4:1, CHCl₃ ·NH₃/IPA) to provide impure 31-4 which was rechromatographed (silica, 9:1EtOAc/IPA) to give 31-4 as a colorless foam.

Rf 0.33 (silica, 9:1 EtOAc/IPA).

¹ H NMR (400 MHz, CD₃ OD) δ 8.33 (dd, J=5, 1 Hz, 1H), 7.95 (dd, J=8, 1Hz, 1H), 7.81-7.84 (m, 4H), 7.70-7.78 (m, 3H), 7.44-7.52 (m, 3H),7.25-7.30 (m, 2H), 4.15 (dd, J=8, 6 Hz, 1H), 3.69 (dd, J=14, 6 Hz, 1H),3.51 (dd, J=8 Hz, 14 Hz, 1H), 1.12 (s, 9H). ##STR81## 4- 2-(1H-Imidazo4,5-b!pyridin-2-yl)ethenyl!benzoyl-2(S)-phenyl-sulfonylamino-β-alanine(31-5)

A CH₂ Cl₂ solution (20 mL) of 31-4 (220 mg, 0.4 mmol) and TFA (5 mL) wasstirred under ambient conditions for 5 h and concentrated. Flashchromatography (silica 9:0.5:0.5, EtOH/H₂ O/NH₄ OH) gave 31-5 as asolid.

¹ H NMR (400 MHz, CD₃ OD/NaOD) δ 8.08 (m, 1H), 7.81-7.87 (m, 5H),7.68-7.75 (m, 3H), 7.33-7.37 (m, 4H), 6.98 (m, 1H), 3.65-3.72 (m, 2H),3.32 (m, 1H). ##STR82## 4- 2-(1H-Imidazo4,5-b!pyridin-2-yl)ethyl!benzoyl-2(S)-phenyl-sulfonylamino-β-alanine(31-6)

A mixture of 31-5 (90 mg, 0.18 mmol), 10% Pd/C (50 mg), 1N NaOH (2 mL)and CH₃ OH (20 mL) was hydrogenated at 1 atm for 18 h. After filtrationand concentration the residue was neutralized with 10% HCl and the solidchromatographed (silica, 19:1 EtOH/NH₄ OH) to provide 31-6 as a fluffysolid after trituration with aqueous TFA.

Rf 0.48 (19:1 EtOH/NH₄ OH).

¹ H NMR (400 MHz, CD₃ OD) δ 8.29 (dd, J=5, 1 Hz, 1H), 7.91 (dd, J=8, 1Hz, 1H), 7.82 (m, 2H), 7.67 (d, J=8H, 2H), 7.38-7.48 (m, 3H), 7.30 (d,J=8, 1 Hz, 2H), 7.25 (m, 1H), 3.87 (m, 1H), 3.65 (m, 1H), 3.53 (m, 1H),3.26 (m, 2H). ##STR83## Ethyl 4-2-(1,8-Naphthyridin-7-yl)ethenylbenzoate (32-3)

An ethanol solution (10 mL) of 32-1 (260 mg, 2.1 mmol) (Syn. Comm.17(14), 1695(1987), 32-2 (435 mg, 2.1 mmol) (Tet. Lett. 34(4), 653(1993)and 20% KOH (100 ml) was refluxed for 6 hours. The reaction wasconcentrated to dryness and the residue partitioned between EtOAc and H₂O. The organic layer was washed with brine and dried (MgSO₄). Filtrationand evaporation provided a yellow solid which was purified by flashchromatography (silica, 4:1 EtOAc/hexane) to give 32-3 as a creamcolored solid.

Rf 0.21 (silica, 3/1 EtOAc/hexane).

¹ H NMR (300 MHz, CDCl₃) δ 9.12 (dd, J=4, 2 Hz, 1H), 8.15-8.21 (m, 2H),8.02-8.11 (m, 3H), 7.66-7.72 (m, 3H), 7.48 (d, J=16 Hz, 1H), 7.45 (dd,J=8, 4 Hz, 1H), 4.39 (q, J=7 Hz, 2H), 1.41 (t, J=7 Hz, 3H). ##STR84## 4-2-(1,8-Naphthyridin-7-yl)ethenylbenzoic acid (32-4)

A methanol solution (100 mL) of 32-3 (420 mg, 1.38 mmol) and 1N NaOH(13.8 mL, 13.8 mmol) was stirred at ambient conditions for 18 hrs and atreflux for 2 hrs. The reaction was concentrated to dryness and theresidue dissolved in H₂ O and the solution acidified with 1M NaHSO₄solution to give 32-4 as a pale yellow solid after filtration.

¹ H NMR (300 MHz, CD₃ OD) δ 9.05 (m, 1H), 8.43 (d, J=8 Hz, 2H),8.04-8.10 (m, 2H), 7.96-8.01 (m, 2H), 7.83 (d, J=8 Hz, 2H), 7.61 (m,2H). ##STR85## 4-2-(1,8-Naphthyidin-7-yl)ethenyl)benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butylester (32-5)

To a stirred solution of 32-4 (396 mg, 1.38 mmol), 2-1 (556 mg, 1.65mmol), NMM (728 μl, 6.62 mmol), and DMF (10 mL) was added BOP (732 mg,1.65 mmol). After 18 h the reaction was concentrated to dryness and theresidue partitioned between EtOAc and H₂ O. The organic layer was washedwith sat. NaHCO₃ solution, brine, dried (MgSO₄) and concentrated. Flashchromatography (silica, 3:2 CH₂ Cl₂ /acetone) gave 32-5 as a yellowfoam.

Rf 0.34 (silica, 3:2 CH₂ Cl₂ /acetone).

¹ H NMR (300 MHz, CD₃ OD) δ 9.05 (m, 1H), 8.41 (d, J=8 Hz, 2H),7.95-8.03 (m, 2H), 7.78-7.88 (m, 6H), 7.47-7.62 (m, 5H), 4.16 (m, 1H),3.71 (m, 1H), 3.54 (m, 1H), 1.21 (s, 9H). ##STR86## 4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester (32-6)

A mixture of 32-5 (670 mg, 1.2 mmol), 10% Pd/C (335 mg) and ethanol (50mL) was stirred under a hydrogen atmosphere (1 atm) for 18 h. Filtrationfollowed by concentration gave a yellow foam. Flash chromatography(silica, 97:3 CH₂ Cl₂ /CH₃ OH gave 32-6 as a colorless foam.

Rf 0.26 (silica, 97:3 CH₂ Cl₂ /CH3OH).

¹ H NMR (300 MHz, CD₃ OD) δ 7.82 (d, J=7 Hz, 2H), 7.65 (d, J=8 Hz, 2H),7.42-7.54 (m, 3H), 7.25 (d, J=8 Hz, 2H), 7.08 (d, J=7 Hz, 1H), 6.29 (d,J=7 Hz, 1H), 4.12 (dd, J=8, 6 Hz, 1H), 3.66 (dd, J=12, 6 Hz, 1H), 3.50(dd, J=12, 8 Hz, 1H), 3.37 (t, J=6 Hz, 2H), 2.97 (t, J=6 Hz, 2H), 2.81(t, J=6 Hz, 2H), 2.68 (t, J=6 Hz, 2H), 1.86 (m, 2H), 1.23 (s, 9H).##STR87## 4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine(32-7)

A solution of 32-6 (221 mg, 0.39 mmol), TFA (5 mL) and CH₂ Cl₂ (50 mL)was stirred under ambient conditions for 18 h. The reaction wasconcentrated and the solid residue purified by flash chromatography(silica, 19:1 EtOH/NH₄ OH) to give 32-7 as a pale yellow solid.

Rf 0.63 (silica, 19:1 EtOH/NH₄ OH).

¹ H NMR (300 MHz, CD₃ OD) δ 7.82 (d, J=7 Hz, 2H), 7.69 (d, J=8 Hz, 2H),7.28-7.34 (m, 3H), 7.25 (d, J=8 Hz, 2H), 7.08 (d, J=7 Hz, 1H), 6.29 (d,J=7 Hz, 1H), 3.78 (m, 1H), 3.58-3.70 (m, 2H), 3.38 (t, J=6 Hz, 2H), 2.97(t, J=6 Hz, 2H), 2.81 (t, J=6 Hz, 2H), 2.68 (t, J=6 Hz, 2H), 1.86 (m,2H). ##STR88## 4-2-(1,8-Naphthyridin-7-yl)ethenyl!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alanineethyl ester (33-2)

Following the procedure for coupling 32-4 to 2-1, 32-4 (2.2 g, 7.96mmol) was coupled to 35-2 (4.24 g, 9.55 mmol). Flash chromatography(silica, 3:2 Acetone/CH₂ Cl₂) gave 33-2 as a pale yellow foam.

Rf 0.31 (silica, 1:1 acetone/CH₂ Cl₂).

¹ H NMR (300 MHz, CD₃ OD) δ 9.05 (m, 1H), 8.41 (d, J=8 Hz, 2H),7.95-8.04 (m, 2H), 7.77-7.86 (m, 6H), 7.55-7.64 (m, 5H), 4.24 (m, 1H),3.91 (q, J=7 Hz, 2H), 3.70 (m, 2H), 3.57 (m, 2H), 1.06 (t, J=7 Hz, 3H).##STR89## 4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)phenylsulfonylamino-β-alanineethyl ester (33-3)

A mixture of 33-2 (1.3 g, 2.45 mmol), 10% Pd/C (650 mg) and ethanol (100ml) was stirred under a hydrogen atmosphere (1 atm) for 18 hr.Filtration followed by concentration gave a yellow foam which waspurified by flash chromatography (silica, 49:1 EtOAc/EtOH·NH₃) toprovide 33-3 as a pale yellow solid.

Rf 0.42 (silica, 49:1 EtOAc/NH₃ saturated EtOH·NH₃).

¹ H NMR (300 MHz, CD₃ OD) δ 7.81 (d, J=7 Hz, 2H), 7.64 (d, J=8 Hz, 2H),7.40-7.56 (m, 3H), 7.25 (d, J=8 Hz, 2H), 7.14 (d, J=7 Hz, 1H), 6.33 (d,J=7 Hz, 1H), 4.19 (t, J=6 Hz, 1H), 3.89 (q, J=7 Hz, 2H), 3.63 (m, 1H),3.53 (m, 1H), 3.39 (t, J=6 Hz, 2H), 2.99 (t, J=8 Hz), 2.83 (t, J=8Hz,2H), 2.69 (t, J=6 Hz, 2H), 1.87 (m, 2H), 1.04 (t, J=7 Hz, 3H). ##STR90##Ethyl 2(S)-N.sub.α -Cbz-2,3-diaminopropionate hydrochloride (34-2)

34-1 (5 g, 21 mmol) was dissolved in 100 mL EtOH and cooled to 0° C.SOCl₂ (9.2 mL, 126 mmol) was added followed by removal of the coolingbath. After 6 hours, the reaction was concentrated to provide 34-2 as awhite solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.35 (m, 5H), 5.14 (s, 2H), 4.44 (m, 1H),4.22 (q, J=7 Hz, 2H), 3.43 (m, 1H), 3.20 (m, 1H), 1.25 (t, J=7 Hz, 3H).##STR91## Ethyl 2(S)-N.sub.α -Cbz-N.sub.β -Boc-2,3-diaminopropionate(34-3)

34-2 (2 g, 6.6 mmol) was dissolved in 60 mL CH₃ CN. NEt₃ (1 mL, 7.2mmol) was added followed by BOC₂ O (1.58 g, 7.3 mmol). After two hours,the reaction was concentrated, diluted with EtOAc, washed with sat.NaHCO₃, 10% KHSO₄ and brine, dried (MgSO₄), filtered and concentrated toprovide 34-3 as a clear oil.

TLC Rf 0.87 (silica, 80% EtOAc/hex).

¹ H NMR (300 MHz, CDCl₃) δ 7.35 (s, 5H), 5.75 (bs, 1H), 5.12 (s, 2H),4.81 (bs, 1H), 4.39 (m, 1H), 4.19 (m, 2H), 3.56 (m, 2H), 1.42 (s, 9H),1.29 (q, J=7 Hz, 3H). ##STR92## Ethyl 2(S)-N.sub.β-Boc-2,3-diaminopropionate (34-4)

34-3 (2.4 g, 6.6 mmol) with 10% Pd/C (240 mg) in EtOAc (35 mL) wasstirred under a H₂ atmosphere for 20 hours. The reaction was filteredthrough a celite pad and concentrated to provide 34-4 as a clear oil.

TLC Rf 0.13 (silica, 80% EtOAc/hex).

¹ H NMR (300 MHz, CDCl₃) δ 5.00 (bs, 1H), 4.19 (m, 2H), 3.55 (m, 2H),3.25 (m, 1H), 1.44 (s, 9H), 1.29 (q, J=7 Hz, 3H). ##STR93##Ethyl-2(S)-N.sub.α -(1(S)10-camphorsulfonylamino-N.sub.β-Boc-2,3-diaminopropionate (34-5)

Amine 34-4 (760 mg, 3.27 mmol) was dissolved in 35 mL CH₂ Cl₂ and cooledto 0° C. NMM (755 μL, 6.87 mmol) and 10(+) camphorsulfonyl chloride(1.23 g, 4.9 mmol) were added. After stirring at 0° C. for one hour, thereaction was concentrated, then diluted with EtOAc, washed with H₂ O,sat. NaHCO₃, 10% KHSO₄ and brine, dried (MgSO₄), and concentrated to anoil. Flash chromatography (silica, 25-40% EtOAc/hexanes) provided 34-5as a clear oil.

TLC Rf 0.66 (silica, 50% EtOAc/hexanes).

¹ H-NMR (300 MHz, CDCl₃) δ 6.37 (d, J=8 Hz, 1H), 4.99 (bt, 1H), 4.32 (m,1H), 4.23 (q, J=8 Hz, 2H), 3.56 (m, 3H), 3.0 (d, J=15 Hz, 1H), 2.4 (m,1H), 2.05 (m, 4H), 1.43 (s, 9H), 1.30 (t, J=7 Hz, 3H), 1.00 (s, 3H),0.91 (s, 3H). ##STR94## Ethyl-2(S)-N.sub.α-(1(S)10-camphorsulfonylamino)-2,3-diaminopropionate hydrochloride(34-6)

Ester 34-5 (900 mg, 2.18 mmol) was dissolved in 15 mL EtOAc and cooledto 0° C. HCl (g) was bubbled through the reaction mixture for 15minutes. The reaction was removed from the cooling bath and purged withAr (g) for 20 minutes followed by concentration to provide 34-6 as afoamly solid.

TLC Rf 0.05 (silica, 20% MeOH/EtOAc).

¹ H-NMR (300 MHz, CDCl₃): δ 4.75 (m, 1H), 4.26 (q, J=7 Hz, 2H), 3.50 (m,4H), 2.40 (m, 3H), 1.98 (m, 4H), 1.30 (t, J=7 Hz, 3H), 1.04 (s, 3H),0.91 (s, 3H). ##STR95## 4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)1(S)10-camphorsulfonylamino! β-alanine ethyl ester (34-8)

34-7 (Scheme 37) (200 mg, 0.627 mmol), amine 34-6 (240 mg, 0.69 mmol),NMM (345 μL, 3.13 mmol) and BOP reagent (332 mg, 0.75 mmol) werecombined in 5 mL CH₃ CN. After stirring overnight, the reaction wasconcentrated, then diluted with EtOAc, washed with H₂ O, sat. NaHCO₃ andbrine, dried (MgSO₄), filtered and concentrated. Flash chromatography(silica, EtOAc) provided 34-8 as an off-white foamy solid.

TLC Rf 0.13 (silica, EtOAc).

¹ H NMR (300 MHz, CDCl₃) δ 7.70 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H),7.03 (d, J=7 Hz, 1H), 6.72 (t, J=5 Hz, 1H), 6.5 (bm, 1H), 6.28 (d, J=7Hz, 1H), 4.79 (s, 1H), 4.42 (bs, 1H), 4.25 (q, J=7 Hz, 2H), 4.04 (m,1H), 3.85 (m, 1H), 3.55 (d, J=15 Hz, 1H), 3.41 (m, 2H), 3.00 (m, 3H),2.82 (t, J=4 Hz, 2H), 2.69 (t, J=6 Hz, 2H), 2.04 (m, 8H), 1.58 (bs, 3H),1.31 (t, J=7 Hz, 3H), 1.00 (s, 3H), 0.90 (s, 3H). ##STR96## 4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)-1(S)10-camphorsulfonylamino! β-alanine (34-9)

34-8 (250 mg, 0.409 mmol) was dissolved in 4 mL EtOH, 1M NaOH (1.02 mL,1.02 mmol) was added and the reaction mixture was stirred for two hours.The reaction mixture was neutralized with 1N HCl and then concentratedto a foamy solid. Flash chromatography (silica, 18:10:1:1 EtOAc/EtOH/NH₄OH/H₂ O) provided 34-9 as a slightly yellow solid.

TLC Rf 0.49 (silica, 12:10:1:1 EtOAc/EtOH/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, DMSO) δ 8.48 (bt, 1H), 7.72 (d, J=8 Hz, 2H), 7.55 (bs,1H), 7.28 (d, J=8 Hz, 2H), 7.02 (d, J=7 Hz, 1H), 6.37 (s, 1H), 6.26 (d,J=7 Hz, 1H), 4.13 (s, 1H), 3.54 (m, 3H), 3.37 (m, 2H), 2.94 (m, 3H),2.73 (t, J=7 Hz, 2H), 2.6 (t, J=6 Hz, 2H), 2.3 (m, 3H), 2.02 (m, 1H),1.89 (m, 2H), 1.75 (m, 2H), 1.49 (m, 1H), 1.37 (m, 1H), 1.05 (m, 1H),0.95 (s, 3H), 0.66 (s, 3H). ##STR97## 4-Ethynylbenzoic acid (35-1)

A solution of ethyl ester 29-1 (9.06 g, 36.8 mmol) and aqueous 1N NaOHsolution (92 mL, 92 mmol) in MeOH (300 mL) was stirred overnight. Themixture was concentrated. The residue was dissolved in water thenacidified with 6N HCl before extracting twice with EtOAc. The organiclayers were combined and washed with 5% KHSO₄ solution and brine, thendried (MgSO₄) and concentrated to give 1-1 as a brown solid.

TLC Rf 0.38 (silica, 10% iPrOH/EtOAc).

¹ H NMR (300 MHz, d₆ -DMSO) δ 7.93 (d, J=9 Hz, 2H), 7.60 (d, J=9 Hz,2H), 4.46 (s, 1H). ##STR98## Ethyl 2(S)-phenylsulfonylamino-β-alaninep-toluenesulfonate (35-2)

Acid 2-1b (13.20 g, 54.1 mmol) was suspended in 500 mL EtOH, p-TsOH--H₂O (11.3 g, 59 mmol) was added and the mixture was heated at refluxovernight. After distilling off the solvent, fresh EtOH was added anddistilled off, then more EtOH was added and the mixture was distilled to100 mL at which point 800 mL ether was added. After cooling to 4°,solvent was decanted from the gum which was rinsed with additionalether, and dried, providing 35-2 as a hygroscopic glass. Additional 35-2was recovered from the solvent phase by concentration and trituratingwith ether (2×).

¹ H NMR (400 MHz, D₂ O) δ 7.91 (d, J=8 Hz, 2H), 7.75 (t, J=8 Hz, 1H),7.70 (d, J=8 Hz, 2H), 7.65 (t, J=8 Hz, 2H), 7.37 (d, J=8Hz, 2H), 4.42(dd, J=10, 4 Hz, 1H), 3.86 (t, J=7 Hz, 2H), 3.50 (dd, J=13,5 Hz, 1H),3.20 (dd, J=13, 10 Hz, 1h), 2.40 (s, 3H), 0.99 (t, J=7 Hz, 3H).##STR99## 4-Ethynylbenzoyl-2(S)-phenylsulfonylamino-β-alanine ethylester (35-3)

4-Ethynylbenzoic acid (35-1) (3.10 g, 21.2 mmol), 35-2 (8.58 g, 19.3mmol), NMM (8.49 mL, 7.72 mmol), HOBT (3.39 g, 25.1 mmol), and EDC (4.81g, 25.1 mmol) were combined in 96 mL DMF and stirred overnight. Thereaction was concentrated, residue was diluted with EtOAc and washedwith water (2×) and brine, dried (Na₂ SO₄), filtered, and concentrated.Flash chromatography (silica, 45-50% EtOAc/Hexane) gave 35-3 as a whitesolid.

TLC Rf 0.27 (silica, 45% EtOAc/Hexane).

¹ H-NMR (300 MHz, d₆ -DMSO) δ 8.63 (t, J=6 Hz, 1H), 8.47 (br s, 1H),7.75 (m, 4H), 7.52 (m, 5H), 4.39 (s, 1H), 4.11 (t, J=7 Hz, 1H), 3.78 (q,J=7 Hz, 2H), 3.44 (m, 3H), 0.94 (t, J=7 Hz, 3H). ##STR100## 4-(3-Aminoisoquinolin-1-yl)ethynyl!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alanineethyl ester (35-4)

Ethyl ester 35-3 (0.50 g, 1.25 mmol), 3-amino-1-bromoisoquinoline (0.279g, 1.25 mmol), triethylamine (0.697 mL, 5.00 mmol), CuI (10 mg, 0.053mmol), and (Ph₃ P)₂ PdCl₂ (20 mg, 0.028 mmol) were combined in 5 mLacetonitrile in a sealed pressure tube under Ar and heated to 100° C.overnight. The dark solution was cooled and diluted with EtOAc, thenwashed with water (2×) and brine, dried (MgSO₄), filtered, andconcentrated. Flash chromatography (silica, 75% EtOAc/Hexane) gave 35-4as a greenish foam.

TLC Rf 0.21 (silica, 75% EtOAc/Hexane).

¹ H NMR (400 MHz, CDCl₃) δ 8.29 (d, J=8 Hz, 1H), 7.88 (d, J=9 Hz, 2H),7.82 (d, J=8 Hz, 2H), 7.77 (d, J=8 Hz, 2H), 7.55 (m, 5H), 7.35 (tm, J=7Hz, 1H), 7.27 (s, 1H), 6.80 (s, 2H), 5.80 (br s, 1H), 4.56 (s, 2H), 4.11(m, 3H), 3.97 (m, 1H), 3.68 (m, 1H), 1.17 (t, J=7 Hz, 3H). ##STR101## 4-(3-Aminoisoquinolin-1-yl)ethynyl!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alaninetrifiuoroacetate (35-5)

A solution of ester 35-4 (0.46 g, 0.85 mmol) in dioxane (4 mL) and 6NHCl (8.5 mL) was heated to 60° C. overnight. Concentration yielded anorange solid. Prep. HPLC (C₁₈, 0.1% TFA H₂ O/CH₃ CN) followed bylyophilization gave trifiuoroacetate 35-5 as an orange solid.

TLC Rf 0.25 (silica, 33:20:1:1 EtOAc:EtOH:NH₄ OH:H₂ O).

¹ H NMR (400 MHz, CD₃ OD) δ 8.27 (dm, J=9 Hz, 1H), 7.87 (m, 6H), 7.68(m, 2H), 7.50 (m, 4H), 7.15 (s, 1H), 4.24 (dd, J=9, 5 Hz, 1H), 3.79 (m,1H), 3.51 (m, 1H). ##STR102## 4-2-(3-Aminoisoquinolin-1-yl)ethyl!benzoyl-2(S)-phenylsulfonyl-amino-.beta.-alaninetrifluoroacetate (35-6)

A mixture of acetylene 35-5 (0.085 g, 0.13 mmol) and 10% palladium oncarbon (40 mg) in aqueous 0.1 N NaOH was stirred under a hydrogenballoon overnight. The suspension was filtered through celite andconcentrated to a dark oil. Prep. HPLC (C₁₈, 0.1% TFA H₂ O/CH₃ CN)followed by lyophilization gave 35-6 as a fluffy, yellow solid.

TLC Rf 0.51 (silica, 22:1:1 iPrOH/NH₄ OH/H₂ O).

¹ H NMR (400 MHz, d₆ -DMSO) δ 8.40 (t, J=6 Hz, 1H), 8.22 (d, J=9 Hz,1H), 8.14 (d, J=9 Hz, 1H), 7.75 (d, J=7 Hz, 2H), 7.68 (m, 3H), 7.60 (m,1H), 7.52 (m, 1H), 7.45 (m, 2H), 7.38 (d, J=8 Hz, 2H), 7.28 (t, J=7 Hz,1H), 6.86 (br, s, 1H), 4.04 (m, 1H), 3.35 (m), 3.11 (t, J=8 Hz, 2H).##STR103## 4-(3-aminopropoxy)benzoic acid methyl ester trifiuoraacetate(36-1)

A CH₂ Cl₂ solution (25 mL) of 8-3 (2.8 g, 8.97 mmol) and TFA (5 mL) wasstirred under ambient conditions for 2 hr. The reaction was concentratedand the residue azeotroped with toluene to give a sticky solid which wastriturated with hexane/ether (1:1) to provide 36-1 as a solid.

¹ H NMR (400 MHz, CD₃ OD) δ 7.97 (d, J=8 Hz, 2H), 7.02 (d, J=8 Hz, 2H),4.19 (t, J=7 Hz, 2H), 3.86 (s, 3H), 3.16 (t, J=7 Hz, 2H), 2.17 (m, 2H).##STR104## 4- 3- 3-(2-nitrophenyl)thioureido!propoxy!benzoic acid methylester (36-3)

An ethanol solution (20 mL) of 36-1 (2.65 g, 8.19 mmol), 36-2 (1.47 g,8.19 mmol) (Lancaster), and Et₃ N (2.28 mL, 16.4 mmol) was stirred underambient conditions for 18 h. The reaction was concentrated and theresidue purified by flash chromatography (silica, 19:1 CH₂ Cl₂ /acetone)to provide 36-3 as a yellow foam.

Rf 0.23 (silica, 19:1 CH₂ Cl₂ /acetone).

¹ H NMR (400 MHz, CDCl₃) δ 8.14 (dd, J=8, 2 Hz, 1H), 7.96 (d, J=8 Hz,2H), 7.58 (m, 1H), 7.23 (m, 1H), 6.81-6.87 (m, 3H), 4.17 (t, J=7 Hz,2H), 3.89 (m, 5H), 2.22 (m, 2H). ##STR105## 4- 3-3-(2-aminophenyl)thioureido!propoxy!benzoic acid methyl ester (36-4)

A methanol solution (150 mL) of 36-3 (3.15 g, 8.08 mmol) was saturatedwith NH₃. 10% Pd/C (2 g) was added and the mixture hydrogenated at 1 atmfor 4 h. Filtration and concentration provided 36-4 as a purple solid.

Rf 0.18 (silica, 19:1 CH₂ Cl₂ /acetone).

¹ H NMR (400 MHz, CDCl₃) δ 7.92 (d, J=8 Hz, 2H), 7.17 (m, 1H), 7.07 (m,1H), 6.72-6.79 (m, 2H), 6.62 (d, J=8 Hz, 2H), 4.05 (t, J=7 Hz, 2H),3.83-3.89 (m, 5H), 2.11 (m, 2H). ##STR106## 4- 3-N-(1H-Benzimidazol-2-yl)amino!propoxy!benzoic acid methyl este (36-5)

A mixture of 36-4 (2.5 g, 7.0 mmol), HgO (3.0 g, 13.9 mmol), sulfur (42mg) and EtOH (50 mL) was refluxed for 2.5 h. Filtration andconcentration gave a brown gum which was purified by flashchromatography (silica, 9:1 CH₂ Cl₂ /CH₃ OH) to provide 36-5 as a tansolid.

Rf 0.29 (silica, 9:1 CH₂ Cl₂ /CH₃ OH).

¹ H NMR (400 MHz, CD₃ OD) δ 7.94 (d, J=9 Hz, 2H), 7.18 (m, 2H), 7.00 (d,J=9 Hz, 2H), 6.96 (m, 2H), 4.19 (t, J=6 Hz, 2H), 3.86 (s, 3H), 3.58 (t,J=6 Hz, 2H), 2.16 (m, 2H). ##STR107## 4- 3-N-(1H•Benzimidazol-2-yl)amino!propoxy!benzoic acid (36-6)

A methanol solution (50 mL) of 4-5 (1.3 g, 4.0 mmol) and 1N NaOH (20 mL,20 mmol) was stirred at 50° C. for 4 h. The reaction was concentratedand the residue acidified with 1M NaHSO₄ solution to provide 4-6 as abeige colored solid.

₁ H NMR (400 MHz, CD₃ OD) δ 7.91 (d, J=9 Hz, 2H), 7.32 (m, 2H), 7.20 (m,2H), 6.95 (t, J=9 Hz 2H), 4.21 (t, J=6 Hz, 2H), 3.62 (t, J=6 Hz, 2H),2.22 (m, 2H). ##STR108## 4- 3-N-(1H-Benzimidazol-2-yl)amino!propoxy!benzoyl-2(S)-phenylsulfonylamino-β-alaninet-butyl ester (36-7)

A DMF solution (10 mL) of 36-6 (311 mg, 1.0 mmol), 2-1 (370 mg,1.1mmol), HOBT (168 mg, 1.1 mmol), NMM (330 μl, 3.0 mmol) and EDC (211mg, 1.1 mmol) was stirred under ambient conditions for 18 h.Concentration and flash chromatography (silica, 85:15 EtOAc/CH₃ OH) gave36-7 as a pale yellow foam.

Rf 0.20 (silica, 85:15 EtOAc/CH₃ OH).

¹ H NMR (400 MHz, CD₃ OD) δ 7.83 (d, J=8 Hz, 2H), 7.73 (d, J=9 Hz, 2H),7.46-7.54 (m, 3H), 7.26-7.30 (m, 2H), 7.10-7.13 (m, 2H), 6.98 (d, J=9Hz, 2H), 4.20 (m, 2H), 3.63 (m, 3H), 3.44 (m, 1H), 3.31 (m, 1H), 2.19(m, 2H), 1.23 (s, 9H). ##STR109## 4- 3-N-(1H-Benzimidazol-2-yl)amino!propoxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine(36-8)

A CH₂ Cl₂ solution (20 mL) of 36-7 (580 mg, 0.97 mmol) and TFA (5 mL)was stirred under ambient conditions for 2 h and at 50° C. for 2 h.Concentration and flash chromatography (silica, 9:0.5:0.5 EtOH/H₂ O/NH₄OH) gave 36-8 as a pale yellow solid.

Rf 0.29 (silica 9.8:0:1:0.1 EtOH/H₂ O/NH₄ OH).

¹ H NMR (400 MHz, CD₃ OD) δ 7.83 (m, 2H), 7.76 (d, J=9 Hz, 2H),7.32-7.34 (m, 3H), 7.17-7.19 (m, 2H), 6.99 (d, J=9 Hz, 2H), 6.85-6.88(m, 2H), 4.20 (t, J=6 Hz, 2H), 3.58-3.65 (m, 4H), 3.36 (m, H), 2.16 (m,2H). ##STR110## Ethyl-4-(2-butanene)benzoate (37-3)

3-Buten-2-ol 37-1 (2.15 mL, 25 mmol), ethyl 4iodobenzoate (37-2) (5.52q, 20 mmol) and NEt₃ (3.5 mL, 25 mmol) were combined in 6 mL of CH₃ CNunder Ar in a pressure tube. Pd(OAc)₂ (19 mg, 0.08 mmol) was added andthe reaction heated to 100° C. for 3 hours. The reaction was cooled,then diluted with Et₂ O, washed with H₂ O, 10% KHSO₄, sat. NaHCO₃ andbrine, dried (MgSO₄) and concentrated to a yellow oil. Flashchromatography (silica, 10% EtOAc/hex) provided 37-3 as a clear oil.

TLC Rf 0.23 (silica, 30% EtOAc/hex).

¹ H NMR (300 MHz, CDCl₃): δ 7.95 (d, J=8 Hz, 2H), 7.25 (d, J=8 Hz, 2H),4.36 (q, J=7 Hz, 2H), 2.95 (t, J=7 Hz, 2H), 2.78 (t, J=7 Hz, 2H), 2.15(s, 2H), 1.38 (t, J=7 Hz, 3H). ##STR111## Ethyl 4-2-(1,8-naphthyridin-7-yl)ethyl!benzoate (37-4)

An ethanol solution of(70 mL) of 37-3 (3.15 g, 14.3 mmol), 32-1 (1.75 g,14.3 mmol) and 20% KOH (2 mL) was refluxed for 18 hours. The reactionwas concentrated to dryness and the residue partitioned between EtOAcand H₂ O. The organic layer was washed with sat. NaHCO₃ and brine, dried(MgSO₄) and concentrated to give a yellow oil. Flash chromatography(silica, 60%-80% EtOAc/hex) provided 37-4 as a yellow solid.

TLC Rf 0.31 (silica, 70% EtOAc/hex).

¹ H NMR (300 MHz, CDCl₃) δ 9.11 (m, 1H), 8.18 (d, J=8 Hz, 1H), 8.08 (d,J=8 Hz, 1H), 7.95 (d, J=8 Hz, 2H), 7.47 (m, 1H), 7.30 (d, J=8 Hz, 2H),4.35 (q, J=7 Hz, 2H), 3.35 (m, 4H), 1.38 (t, J=7 Hz, 3H). ##STR112##Ethyl 4- 2-(1,2,3,4-tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoate(37-5)

A mixture of 37-4 (645 mg. 2.11 mmol), 10% Pd/C (65 mg), and ethanol (10mL) was stirred under a hydrogen atmosphere for 18 hr. Filtrationthrough a celite pad followed by concentration provided by 37-5 as anoff white solid.

TLC Rf 0.75 (silica, 70% EtOAc/hex).

¹ H NMR (300 MHz, CDCl₃) δ 7.94 (d, J=8 Hz, 2H), 7.26 (d, J=8 Hz, 2H),7.03 (d, J=7 Hz, 1H), 6.28 (d, J=7 Hz, 1H), 4.81 (s, 1H), 4.35 (q, J=7Hz, 2H), 3.40 (m, 2H), 3.03 (m, 2H), 2.84 (m, 2H), 2.69 (t, J=6 Hz, 2H),1.93 (t, J=6 Hz, 2H), 1.38 (t, J=7 Hz, 3H). ##STR113## 4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoic acidhydrochloride (34-7)

Ester 37-5 (680 mg, 2.11 mmol) in 10 mL 6N HCl was heated to 50° C. for18 hours. Concentration provided 34-7 as a yellow solid.

¹ H NMR (300 MHz, CD₃ OD) δ 7.93 (d, J=8 Hz, 2H), 7.52 (d, J=8 Hz, 1H),7.31 (d, J=8 Hz, 2H), 6.54 (d, J=8 Hz, 1H), 3.48 (t, J=5 Hz, 2H), 3.03(m, 4H), 2.79 (t, J=6 Hz, 2H), 1.93 (t, J=6 Hz, 2H).

The test procedures employed to measure the bone resorption inhibitingactivity of the compounds of the present invention are described below.

BONE RESORPTION-PIT ASSAY

When osteoclasts engage in bone resorption, they will literally causethe formation of pits in the surface of bone that they are acting upon.Therefore, when testing compounds for their ability to inhibitosteoclasts, it is useful to measure the ability of osteoclasts toexcavate these resorption pits when the inhibiting compound is present.

Consecutive cross sections (4.4 ×4.4 ×0.2 mm) of bovine femur were cutfrom the diaphysis with a low-speed diamond saw (Isomet, Beuhler, Ltd.,Lake Bluff, IL.) by the method of Arnett and Dempter. Endocrinology,120: 602-608.

Prior to incubation with osteoclasts, slices were rehydrated in 0.1 mlcomplete medium 199 in a 48-well plate (Costar, Cambridge, MA) overnightin the presence of twice the desired dose of compound being tested.

Osteoclasts were isolated from the long bones of 1 to 3-day-old rats(Spmgue-Dawley) by adaptations of methods used by Chambers, et al., J.Cell Sci., 66: 383-399.

Femora, tibiae, and humeri were split and minced with scalpel bladesinto 2-5 ml Medium 199 (GIBCO, New York). The resulting suspension wasgently pipetted (60 times with a wide-bore pipet and then aliquoted ontopetri dished (Costar) or bone slices (0.1 ml per slice). Cells wereallowed to settle for 30-40 minutes at 37° C. in moist CO₂ -air beforegently washing and reincubation in undiluted incubation medium.Osteoclast yields varied from 300 to 1400 per rat and typicallycomprised 1% or less of the total cell population.

Osteoclasts were counted at the day of isolation and after 1 day ofincubation by phase-constrast microscopy (Nikon Diaphot). Total attachedcells were counted 50-70 h. after isolation with a Coulter counter(model ZM, Coulter Electronics, Inc., Hialeah, Fla.). Cell counts ofcontrols varied from 3.352 ×10₄ to 2.322 ×10₅ per well. Countingmononuclear cells at the time of isolation was not practical because ofmatrix and cell debris that could not be completely eliminated.

Bone slices exposed to osteoclasts for 20 h. after isolation wereprocessed for staining by ultrasonication (twofold, 15 s, Branson) in0.25M ammonium hydroxide before fixation (20 minutes) in 2.5%glutaraldehyde, 0.1M cacodylate, pH 7.4 (EM Supplies, Fort Washington,Pa). Samples were dehydrated in ethanol (40, 70, and 100%; 5 minutes),air dried for 2 h., and then stained for 4 minutes with filtered 1%toluidine blue and 1% borax (Sigma, St. Louis, Mo). Samples used tocount osteoclasts were processed as earlier without ultrasonication inammonium hydroxide.

A fluorescence microscope (Microphot, Nikon) was adapted for reflectedlight microscopy by inserting a λ4 plate between cross polarizers in theepi mode. Fluorescence objectives of long working distance withadjustable correction collars (10 ×, 20 ×, Nikon) were fitted withrotable λ4 plates (Polaroid Corp., Massachusetts) mounted as the frontelement. Correction collars were necessary 20x objectives and higher tocorrect for the presence of the λ4 plate and the absence of a coverslip.Coverslips were not used to eliminate stray reflections below the λ4plate. Immersion oil (Nikon) was added between the objective front lensand λ4 to minimize reflections at this interface. Oil was not placedbetween objective and specimen.

Bone slices were scanned for resorption pits by rotating the λ4 plate0°-45° with respect to the plane of polarization in epi-tungstenillumination. Altematively, Hg illumination (HBO 100 w, Nikon) was usedwith the λ4 plate fixed at 45° while intelnnittently viewing stainedimages by transmission brightfield microscopy with an NCB 10 filter(Nikon).

Quantitation of resorbed areas of bone slices examined by bright-field,RLM, and SEM was achieved through digital image processing (Magiscan 2A,Joyce Loebl, NY) of video images (Newvicon or SIT, Dage-MTI, Inc.Michigan City, Ind.) fed through a NTSC/PAL digital standards converter(CEL P156, James Grunder and Assoc., Inc., Mission, Kans.).

Osteoclasts were processed for immunofluorescence by briefly finsingcoverslips in buffer S (60 mM Pipes, pH 6.9; 25 mM Hepes; 10 mM EGTA;and 2 mM MgCl₂) at 37° C. and then fixing for 2 minutes in buffer S+10%formaldehyde, pH 7.0. Cells were permeabilized in buffer S+0.5% TritonX-100 and then finsed. Specimens were incubated (30 minutes) inappropriate antibody or rhodamine-phalloidine (Molecular Probes, Eugene,Oreg.) followed by. fluorescein goat antirabbit antibody (Cappel).

The bone slice assay is used to examine the effect of the compound ofinterest on the activity of isolated osteoclasts from rat long bones.

The number of resorption pits formed by osteoclasts after 1 day onconsecutive cross sections of bovine femur was first compared to controlsamples by the method of Arnett and Dempster, Endocrinology 120:602-608,and then plotted as a function of concentration of the compound ofinterest.

The appropriateness of extrapolating data from this assay to utility anduse in mammalian (including himan) disease states is supported by theteaching found in Sato, M., et at., Journal of Bone and MineralResearch, Vol. 5, No. 1, 1990. That article teaches that certainbisphosphonates have been used clinically and appear to be effective inthe treatment of Paget's disease, hypercalcemia of malignancy,osteolytic lesions produced by bone metastases, and bone loss due toimmobilization or sex hormone deficiency. These same bisphosphonates arethen tested in the resorption pit assay described above to confirm acorrelation between their known utility and positive performance in theassay.

EIB ASSAY

Duong et al., J. Bone Miner. Res., 8:S 378, describe a system forexpressing the human integrin α_(v)β 3. It has been suggested that theintegrin is involved in the attachment of osteoclasts to bone matrix,since antibodies against the integrin, or RGD-containing molecules, suchas echistatin (European Publication 382 451), can effectively block boneresorption.

Reaction Mixture:

1. 175 μl TBS buffer (50 mM Tris·HCl pH 7.2, 150 mM

NaCl, 1% BSA, 1 mM CaCl₂, 1 mM MgCl₂).

2. 25 μl cell extract (dilute with 100 mM octylglucoside buffer to give2000 cpm/25 μl).

3. ¹²⁵ I-echistatin (25 μl/50,000 cpm) (see EP 382 451).

4. 25 μl buffer (total binding) or unlabeled echistatin (non-specificbinding).

The reaction mixture was then incubated for 1 h at room temp. Theunbound and the bound α_(v) β3 were separated by filtration using aSkatron Cell Harvester. The filters (prewet in 1.5% polyethyleneiminefor 10 mins) were then washed with the wash buffer (50 mM Tris HCl, 1 mMCaCl₂ /MgCl₂, pH 7.2). The filter was then counted in a gamma counter.

OCFORM ASSAY

Osteoblast-like cells (1.8 cells), originally derived from mousecalvaria, are plated in CORNING 24 well tissue culture plates in αMEMmedium containing ribo- and deoxyribonucleosides, 10% fetal bovine serumand penicillin-streptomycin. Cells are seeded at 40,000/well in themorning. In the aftemoon, bone marrow cells are prepared from six weekold male Balb/C mice as follows:

Mice are sacrificed, tibiae removed and placed in the above medium. Theends are cut off and the marrow is flushed out of the cavity into a tubewith a 1 mL syringe with a 27.5 guage needle. The marrow is suspended bypipetting up and down with a glass pasteur pipet. The suspension ispassed through two layers of approximately 400 μm mesh stainless steelcloth. The resulting suspension is centrifuged at 350× g for sevenminutes. The pellet is resuspended, and a sample is diluted in 2% aceticacid to lyse the red cells. The remaining cells are counted in ahemacytometer. The cells are pelleted and resuspended at 1×10⁶ cells/mL.50 μL is added to each well of 1.8 cells to yield 50,000 cells/well and1,25-dihydroxy-vitamin D₃ (D₃) is added to each well to a finalconcentration of 10 nM. The cultures are incubated at 37° C. in ahumidified, 5% CO₂ atmosphere. After 48 h, the medium is changed. 72 hafter the addition of bone marrow, test compounds are added with freshmedium containing D₃ to triplicate wells. Compounds are added againafter 48 h with fresh medium containing D₃. After an additional 24 h themedia is removed, cells are fixed with 10% formaldehyde in phosphatebuffered saline for 10 minutes at room temperature, followed by a 1-2minute treatment with ethanol:acetone (1:1) and air dried. The cells arethen stained for tartrate resistant acid phosphatase as follows:

The cells are stained for 10-15 minutes at room temperature with 50 mMacetate buffer, pH 5.0 containing 30 mM sodium tartrate, 0.3 mg/mL FastRed Violet LB Salt and 0.1 mg/mL Naphthol AS -MX phosphate. Afterstaining, the pates are washed extensively with dionized water and airdried. The number of multinucleated, positively staining cells arecounted in each well.

The compounds of the invention have values in the range 0.5-500 nM inEIB and 1-1000 nM in OCFORM.

While the invention has been described and illustrated in reference tocertain preferred embodiments thereof, those skilled in the art willappreciate that various changes, modifications and substitutions can bemade therein without departing from the spirit and scope of theinvention. For example, effective dosages other than the preferred dosesas set forth hereinabove may be applicable as a consequence ofvariations in the responsiveness of the mammal being treated forseverity of bone disorders caused by resorption, or for otherindications for the compounds of the invention indicated above.Likewise, the specific pharmacological responses observed may varyaccording to and depending upon the particular active compound selectedor whether there are present pharmaceutical carriers, as well as thetype of formulation and mode of administration employed, and suchexpected variations or differences in the results are contemplated inaccordance with the objects and practices of the present invention. Itis intended, therefore, that the invention be limited only by the scopeof the claims which follow and that such claims be interpreted asbroadly as is reasonable.

What is claimed is:
 1. A compound of the formula ##STR114## andpharmaceutically acceptable salts thereof, wherein X is selected fromthe group consisting of ##STR115## Y is selected from the groupconsisting of C₁₋₈ alkylene,(CH₂)m--C.tbd.C(CH₂)n, (CH₂)mCR¹ =CR²(CH₂)n, (CH₂)mCR¹ =CR² (CH₂)n^(O), C₀₋₈ alkylene--NR³ --CO--C₀₋₈alkylene, C₀₋₈ alkylene--O--C₀₋₈ alkylene, C₀₋₈ alkylene-NR³ --C₀₋₈alkylene and C₀₋₈ alkYlene-NR³ --C₀₋₈ alkylene--O--; A is selected fromthe group consisting of ##STR116## B is ##STR117## R¹, R², R³ and R⁴ areeach independently selected from the group consisting ofhydrogen, C₁₋₄alkoxy C₀₋₆ alkylene, C₁₋₄ alkoxycarbonyl C₀₋₆ alkylene, C₁₋₆ alkylaminoC₀₋₈ alkylene, C₁₋₆ dialkylamino C₀₋₈ alkylene, amino C₀₋₈ alkylene andaryl C₀₋₈ alkylene; R⁵ is selected from the group consisting ofhydrogen,C₁₋₄ alkoxy C₀₋₆ alkylene, C₁₋₄ alkoxycarbonyl C₀₋₆ alkylene, C₁₋₆alkylamino C₀₋₈ alkylene, C₁₋₆ dialkylamino C₀₋₈ alkylene, amino C₀₋₈alkylene, oxo and aryl C₀₋₈ alkylene; R⁶ and R⁷ are each independentlyselected from the group consisting of:hydrogen, C₀₋₆ alkylamino C₀₋₆alkylene, C₀₋₆ dialkylamino C₀₋₆ alkylene, aryl C₀₋₆alkyloxycarbonylamino C₀₋₆ alkylene, aryl C₀₋₆ alkylsulfonylamino C₀₋₆alkylene, camphorsulfonylamino, and aryl C₀₋₆ alkylcarbonylamino C₀₋₆alkylene; R¹² is selected from the group consisting ofhydroxy, C₁₋₈alkyloxy, C₁₋₆ dialkylaminocarbonylmethoxy and aryl C₁₋₆dialkylaminocarbonylmethoxy; and m and n are integers independentlychosen from 0-6;and the pharmaceutically acceptable salts thereof. 2.The compound of claim 1, and pharmaceutically acceptable salts thereof,whereinY is selected from the group consisting ofC₁₋₂ alkylene,--C.tbd.C--, C₀₋₂ alkylene--NH--CO--, C₀₋₅ alkylene--O--C₀₋₁ alkyleneand --NH--C₂₋₄ alkylene--O--; A is selected from the group consisting of##STR118## R¹ is selected from the group consisting of hydrogen andC₁₋₄alkoxy; R⁶ and R⁷ are each independently selected from the groupconsisting ofhydrogen, --NHCbz, --NHSO₂ Ph, --NHC(O)--Ph, ##STR119## mand n are integers independently chosen from 0-1.
 3. The compound ofclaim 2, and pharmaceutically acceptable salts thereof, selected fromthe group consistingof4(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonyl-amino-β-alaninet-butyl ester,4(2-Aminopyridin-6-ylethynyl)benzoyl-2(S)-phenylsulfonylamino-β-alanine,4-2-(2-Aminopyridin-6-yl)ethyl!benzoyl-2(S)-phenylsulfonylamino-β-alanine,4-2-(2-Aminopyridin-6-yl)ethyloxy!benzoyl-2(S)-phenyl-sulfonylamino-β-alaninet-butyl ester, 4-2-(2-Aminopyridin-6-yl)ethyloxy!benzoyl-2(S)-phenylsulfonylamino-β-alanine,4-2-(1,8-Naphthyridin-7-yl)ethenyl)benzoyl-2(S)phenylsulfonylamino-β-alaninet-butylester, 4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)phenylsulfonylamino-β-alaninet-butyl ester, 4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7yl)ethyl!benzoyl-2(S)phenylsulfonylamino-β-alanine,4-2-(1,8-Naphthyridin-7-yl)ethenyl!benzoyl-2(S)phenylsulfonyl-amino-β-alanineethyl ester, 4-2-(1,2,3,4-Tetrahydro-1,8-naphthyridin-7-yl)ethyl!benzoyl-2(S)phenylsulfonylamino-β-alanine ethyl ester, 4- 2-(1,2,3,4-Tetrahydro-1,8naphthyridin-7-yl)ethyl!benzoyl-2(S) 1 (S) 10camphorsulfonylamino!β-alanine ethyl ester, and 4-2-(1,2,3,4-Tetrahydro-1,8 naphthyridin-7-yl)ethyl!benzoyl-2(S) 1 (S) 10camphorsulfonylamino!β-alanine.
 4. A method of inhibiting the boneresorption activity of mammalian osteoclast cells comprising the step ofadministering a pharmacologically effective amount of a compound ofclaim
 1. 5. A composition comprising a phamacologically effective amountof the compound of claim 1 and a phamaceutically acceptable carrier. 6.A method for inhibiting tumor metastasis in a patient comprising thestep of administering a pharamacologically effective amount of acompound of claim
 1. 7. A method for inhibiting restenosis in a patientcomprising the step of administering a pharamacologically effectiveamount of a compound of claim
 1. 8. A method for inhibiting diabeticretinopathy in a patient comprising the step of administering apharamacologically effective amount of a compound of claim 1.